Controlled Release Dosage Form

ABSTRACT

The present invention provides a simple and improved dose form that is capable of providing a controlled release of GABA B  receptor agonist contained in the core thereof. The invention also provides methods of administering the dosage form and of treating conditions that are therapeutically responsive to GABA B  receptor agonist.

CROSS-REFERENCE TO EARLIER FILED APPLICATION(S)

This application is a continuation of and claims the benefit of U.S.Ser. No. 15/048,743 filed Feb. 19, 2016, which claims the benefit ofprovisional application U.S. 62/130,757 filed Mar. 10, 2015, provisionalapplication U.S. 62/118,910 filed Feb. 20, 2015, provisional applicationU.S. 62/119,017 filed Feb. 20, 2015, and provisional application U.S.62/131,495 filed Mar. 11, 2015, the entire disclosures of which arehereby incorporated by reference.

FIELD OF THE INVENTION

This invention pertains to a delivery device for the controlled deliveryof arbaclofen to an environment of use. More particularly, it pertainsto a controlled release dosage form comprising arbaclofen, wherein thedosage form provides improved efficacy and safety profiles as comparedto other dosage forms. Methods of use thereof are also provided.

BACKGROUND OF THE INVENTION

Spasticity is a common complication in MS (Multiple Sclerosis) andoccurs in up to 84% of patients. The main sign of spasticity isresistance to passive limb movement characterized by increasedresistance to stretching, clonus, and exaggerated deep reflexes. Theassociated features of spasticity, including pain, gait disorders,fatigue, and loss of function, significantly affect patient quality oflife. Data collected from the North American Research Committee on MS(NARCOMS) Patient Registry showed that 34% of over 20,000 MS patientssurveyed experienced moderate, severe, or total limitation of abilitiesdue to spasticity.

Baclofen (racemic baclofen: rac-BAC;(+/−)-4-amino-3-(4-chlorophenyl)butanoic acid) is a GABA_(B) receptoragonist that has been used in the United States since 1977 foralleviating the signs and symptoms of spasticity resulting from multiplesclerosis or spinal cord injury. The mechanism of action of baclofen inspasticity appears to involve agonism at GABA_(B) receptors of thespinal cord (Price et al., Nature 1984, 307(5946), 71-4). Baclofen isbelieved to inhibit the transmission of both monosynaptic andpolysynaptic reflexes at the spinal cord level, possibly byhyperpolarization of primary afferent fiber terminals, with resultantrelief of muscle spasticity. Baclofen was approved for marketing as aracemic compound; however, preclinical studies have since demonstratedthat the antispasticity activity of the drug resides exclusively in theR-isomer (Albright et al., Neurology, 1995, 45(11), 2110-2111).

The active isomer (R)-baclofen ((L)-baclofen; (−)-baclofen; ARBAC) hasalso been studied in several clinical trials for the treatment oftrigeminal neuralgia, affective disorder, and cerebral spasticity. Ithas been demonstrated as providing or suggested to provide efficacy inspasticity, spastic diplegia, spasticity associated with multiplesclerosis, amyotrophic lateral sclerosis, trigeminal andglossopharyngeal neuralgias, spinal cord injury, alcoholism, alcoholaddiction, dependence or alcohol abuse, gastro-esophageal reflux disease(GERD), emesis, cough, narcotic addiction or abuse, nicotine addictionor abuse, neuropathic pain and musculoskeletal pain, nocturnal acidbreakthrough, chronic hiccups, dyspepsia, non-nuclear dyspepsia, gastricmotility disorder, migraine, PTSD (Post-traumatic Stress Disorder),depression, anxiety, and lower urinary tract dysfunction.

Baclofen has a number of significant pharmacokinetic limitationsincluding a narrow window of absorption in the upper small intestine andrapid clearance from the blood. Consequently baclofen in immediaterelease (IR) form is taken three to four times per day to maintain thetherapeutic effects. The product literature for LIORESAL® baclofen (animmediate release tablet formulation) indicates doses can be taken inthe fed or fasting state with no substantial effect upon pharmacokineticparameters. There have been no reports in the literature of baclofen(either in racemic or in optically pure or enriched form) exhibiting anypositive or negative food effect in any dosage form.

Extended release, sustained release, controlled release and modifiedrelease dosage forms containing racemic baclofen (rac-BAC) or(R)-baclofen (ARBAC) are known and reportedly useful for reducing thenumber of dose administrations per day since they increase the period ofdrug release and reduce the Cmax as compared to the IR dosage form.Merino et al (Proc. Eur. Congr. Biopharm. Pharmacokinet., 3^(rd) (1987),2, 564-73) describes studies of intestinal absorption of baclofen in therat small intestine. Merino concludes that administration ofsustained-release forms of the drug or the use of increased doses ofbaclofen to obtain better therapeutic responses may not be suitable forclinical practice in humans.

It would be a significant addition to the art to provide a controlledrelease dosage form suitable for once or twice daily oral administrationthat still provides therapeutic levels of ARBAC for an extended periodof time without having to increase the dose of ARBAC as compared torepeated doses of an IR dosage form in a day.

SUMMARY OF THE INVENTION

The invention provides a controlled release oral dosage form comprisinga GABA_(B) receptor agonist suitable for once or twice daily oraladministration to a subject in need thereof for the treatment of adisease, disorder or condition that is therapeutically responsive to theGABA_(B) receptor agonist. The invention also provides methods of usethereof. The invention provides improved efficacy and safety profilesfor drugs when administered as described herein.

The present invention overcomes some of the disadvantages of the art byproviding a controlled release oral dosage form (AROS or AERT)comprising at least one GABA_(B) receptor agonist, wherein the dosageform provides an improved clinical benefit over other dosage forms. Insome embodiments, the dosage form comprises: a) a core comprising atleast one GABA_(B) receptor agonist and at least one excipient, b) asemipermeable membrane surrounding the core and comprising at least onepreformed passageway. In some embodiments, the controlled release oraldosage form is an osmotic device.

In some embodiments, the controlled release oral dosage form comprises:a) a core comprising at least one GABA_(B) receptor agonist and at leastone water-swellable excipient, b) a semipermeable membrane surroundingthe core and comprising at least one film-forming cellulose ester and atleast one preformed passageway.

Some embodiments of the invention those wherein: a) the core comprisesat least one GABA_(B) receptor agonist and at least two water-swellableexcipients, and the semipermeable membrane surrounding the corecomprises at least two film-forming cellulose esters and at least onepreformed passageway; b) the core comprises at least one GABA_(B)receptor agonist, at least two water-swellable excipients, and at leastone osmotic salt, and the semipermeable membrane surrounding the corecomprises at least two film-forming cellulose esters and at least onepreformed passageway; or c) the core comprises at least one GABA_(B)receptor agonist, at least two water-swellable excipients, at least oneosmotic salt, and at least one binder, and the semipermeable membranesurrounding the core comprises at least two film-forming celluloseesters and at least one preformed passageway.

In some embodiments, the GABA_(B) receptor agonist: a) is (R)-baclofen;b) excludes (S)-baclofen; c) is not racemic baclofen; d) is present insalt form; e) is present in freebase form; f) is present in prodrugform; g) excludes a prodrug form; h) excludes a salt form; or i) is acombination of one or more of the above.

In some embodiments, the at least one water-swellable excipient: a) is awater swellable natural, synthetic or semi-synthetic polymer; b)comprises a single grade or type of polymer; c) comprises two differentgrades of the same type of polymer, meaning the two grades share thesame general chemical structure but differ in one or more physicalproperties; d) comprises two different types of polymer, meaning the twopolymers have different general chemical structure and differ in one ormore physical properties; e) comprises a combination of a cellulosederivative and polyalkylene oxide (PAO); f) comprises a combination ofhydroxypropyl methylcellulose (HPMC) and polyethylene oxide (PEO); g)comprises a major portion of a first grade and a minor portion of asecond grade of the same type of polymer; h) comprises a major portionof a first type and a minor portion of a second type of polymer; i)comprises a major portion of PEO and a minor portion of HPMC; or j) is acombination or one or more of the above.

In some embodiments, the at least one osmotic salt: a) does not have anion in common with the GABA_(B) receptor agonist; b) has an ion incommon with the GABA_(B) receptor agonist; c) is a halide salt; or d) isa combination of one or more of the above.

In some embodiments, the film-forming cellulose ester: a) is present asa single type and grade of cellulose ester polymer; b) is present as acombination of at least two different grades of the same type ofcellulose ester polymer; c) is present as a combination of two differenttypes of cellulose ester polymer; d) is at least one cellulose acetatepolymer; e) is present as at least two different grades of celluloseacetate polymer; f) is present as cellulose acetate Grade 1 (Polymer 1)and Grade 2 (Polymer 2); g) has a formulation as described herein; or h)is a combination of one or more of the above.

In some embodiments, the semipermeable membrane does not rupture duringuse of the dosage form, within 24 hours after administration of thedosage form to a subject or within 24 hours after placement in anaqueous environment of use. In other embodiments, the semipermeablemembrane ruptures during use of the dosage form, within about 0.1 toabout 2 hours, about 0.1 to about 1.5 hours, about 0.1 to about 1 hour,about 0.1 to about 0.75 hours or about 0.1 to about 0.5 hours afteradministration of the dosage form to a subject or after placement in anaqueous environment of use. When the membrane ruptures, it forms atleast one passageway spaced away from the preformed passageway. The atleast one passageway can be formed in the membrane adjacent or along anedge or seam on the surface of the core.

In some embodiments, the core: a) further comprises at least one binder;b) further comprises at least one filler; c) further comprises at leastone antioxidant; d) further comprises at least one glidant; e) furthercomprises at least one lubricant; f) comprises about 5 to about 25 mg,about 5 to about 13 mg, about 13 to about 17 mg, about 17 to about 25mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg or about 25 mg ofGABA_(B) receptor agonist; g) has a formulation as described herein; h)is a unitary core (non-layered construction); h) comprises a mixture ofingredients; i) is a compressed composition; j) excludes a compositionor coat or layer between the core and the semipermeable membrane; or k)is a combination of one or more of the above.

In some embodiments, the dosage form: a) provides a controlled releaseof GABA_(B) receptor agonist for a period of at least 8, at least 10, atleast 12, at least 16, at least 20 and/or up to 24 hours afteradministration; b) provides a release of GABA_(B) receptor agonistcharacterized by an in vitro sigmoidal dissolution profile determined asdescribed herein; c) provides a plasma profile defined by thepharmacokinetic parameters described herein; d) exhibits a positive foodeffect in terms of bioavailability, Tmax, Cmax, AUC_(0-t) and/orAUC_(0-inf) when comparing oral administration of the dosage form in thefed and fasting states; and/or e) further comprises an immediate orrapid release composition comprising GABA_(B) receptor agonist.

In some embodiments, the dosage form: a) comprises a drug-containingcoat exterior to the semipermeable membrane; b) comprises an inert watersoluble or erodible coat composition surrounding the semipermeablemembrane and between the semipermeable membrane and another coat; c)comprises one or more compression coatings and one or more sprayed-oncoatings or membranes exterior to the semipermeable membrane; d)excludes a drug-containing coat exterior to the semipermeable membrane;e) comprises an inert water soluble or erodible coat external to thesemipermeable membrane; or f) comprises at least any two of the above

The present invention further provides a method for treating acondition, disorder or disease that is therapeutically responsive toARBAC, the method comprising administering a controlled release dosageform as described herein. In some embodiments, the condition, disease ordisorder is selected from the group consisting of trigeminal neuralgia,affective disorder, cerebral spasticity, spasticity, spastic diplegia,multiple sclerosis, spasticity associated with multiple sclerosis,amyotrophic lateral sclerosis, trigeminal and glossopharyngealneuralgias, spinal cord injury, alcoholism, alcohol addiction,dependence or alcohol abuse, gastro-esophageal reflux disease (GERD),emesis, cough, narcotic addiction or abuse, nicotine addiction or abuse,neuropathic pain and musculoskeletal pain, nocturnal acid breakthrough,chronic hiccups, dyspepsia, non-nuclear dyspepsia, gastric motilitydisorder, migraine, PTSD (Post-traumatic Stress Disorder), depression,anxiety, and lower urinary tract dysfunction.

In some aspects, the dosage form of the invention exhibits a substantialpositive food effect, whereby it provides an increased Cmax and AUC whenadministered orally in the fed state as compared to the fasting state.The positive food effect can be used to alter the dosing regimen of thedosage form. In some embodiments, the invention provides a method ofadministering ARBAC to a subject in need thereof, the method comprising:a) orally administering a first dose of an extended release dosage formof the invention in the fed state, and b) orally administering a seconddose of an extended release dosage form of the invention in the fastingstate.

In some embodiments, the dosage form provides a majority of drug releasein the upper portion of the GI tract. In some embodiments, a majority ofthe drug is released in the small intestine, or a majority of the drugis released at least in the duodenum and jejunum.

In some embodiments, the invention provides a method of administeringARBAC to a subject in need thereof, the method comprising: a) orallyadministering a first dose of ARBAC in an extended release dosage formof the invention in the fed state, and b) orally administering a seconddose of ARBAC in an extended release dosage form of the invention in thefasting state, wherein the first and second doses are administered about8 to about 16 hours apart.

In some embodiments, the invention provides a method of administeringARBAC to a subject in need thereof, the method comprising: a) orallyadministering a first dose of ARBAC in an extended release dosage formin the fed state, and b) orally administering a second dose of ARBAC inan extended release dosage form in the fasting state, wherein at leastone of the dosage forms exhibits a substantial positive food effect.

In some embodiments, the invention provides a method of administeringARBAC to a subject in need thereof, the method comprising: a) orallyadministering a first dose of ARBAC in an extended release dosage formin the fed state, and b) orally administering a second dose of ARBAC inan extended release dosage form in the fasting state, wherein the firstand second dosage forms are the same and exhibit a substantial positivefood effect.

In some embodiments, the invention provides a method of administeringARBAC to a subject in need thereof, the method comprising: a) orallyadministering a first dose of ARBAC in an extended release dosage formin the fed state, and b) orally administering a second dose of ARBAC inan extended release dosage form in the fasting state, wherein the firstand second dosage form are the same and exhibit a substantial positivefood effect, and the first and second doses are administered about 8 toabout 16 hours apart.

In some embodiments, the invention provides a method of administeringARBAC to a subject in need thereof, the method comprising: a) orallyadministering a first dose of ARBAC in a first extended release dosageform in the fed state, and b) orally administering a second dose ofARBAC in a second extended release dosage form in the fasting state,wherein the first and second dosage forms comprise different doses ofARBAC, the first dosage form exhibits a substantial positive foodeffect, and the first and second doses are administered about 8 to about16 hours apart.

In some embodiments, the invention provides a method of administeringARBAC to a subject in need thereof, the method comprising: a) orallyadministering a first dose of ARBAC in an extended release dosage formin the fed state, and b) orally administering a second dose of ARBAC inan extended release dosage form in the fasting state, wherein: a) thefirst and second dosage form are the same and exhibit a substantialpositive food effect; and b) the first dose is greater than the seconddose. In some embodiments, the first dose is at least 1.2-fold, at least1.5-fold, at least 1.75-fold or at least 2-fold greater than the seconddose.

In some embodiments, the invention provides a method of administeringARBAC to a subject in need thereof, the method comprising: a) orallyadministering a first dose of ARBAC in an extended release dosage formin the fed state, and b) orally administering a second dose of ARBAC inan extended release dosage form in the fasting state, wherein: a) thefirst and second dosage form are the same and exhibit a substantialpositive food effect; and b) the first dose is lower than the seconddose. In some embodiments, the first dose is at least 1.2-fold, at least1.5-fold, at least 1.75-fold or at least 2-fold lower than the seconddose.

The extended release dosage form comprises a dose of ARBAC. In someembodiments, the extended release dosage form exhibits a substantialpositive food effect. In some embodiments, the extended release dosageform provides a reduced Cmax and/or AUC as compared to oraladministration of a reference immediate release dosage form comprisingthe same dose of ARBAC, even if the ARBAC is present as part of rac-BAC.In some embodiments, the extended release dosage form provides a reducedCmax and about the same AUC as compared to oral administration of areference immediate release dosage form comprising the same dose ofARBAC and still provides substantially the same or an improved clinicalbenefit over the immediate release dosage form.

In some embodiments, the first dose is administered during the first12-hour period of a 24-hour period and the second dose is administeredduring the second 12-hr period of the same 24-hour period. In someembodiments, the first dose is administered during the second 12-hourperiod of a 24-hour period and the second dose is administered duringthe first 12-hr period of the same 24-hour period. In some embodiments,the first and second doses are administered about 8 to about 16 hours,about 9 to about 15, about 10 to about 14, about 11 to about 13 or about12 hours apart. In some embodiments, the first dose is administered inthe morning hours, and the second dose is administered in the evening ornighttime hours. In some embodiments, the first dose is administered inthe evening or nighttime hours, and the second dose is administered inthe morning hours. In some embodiments, the first dose is approximatetwice the amount of the second dose. In some embodiments, the method ofthe invention is repeated daily.

The order of administration of the first dose and second dose can bereversed as desired in any embodiment of the invention.

Another aspect of the invention provides a method of changing thecurrent method of treatment of a subject undergoing daily treatment withone or more ARBAC or rac-BAC doses to a second method of treatment, thesecond method of treatment comprising: administering ARBAC to thesubject according to one or more of the methods described herein.

In some embodiments, the second method of treatment comprises: a) orallyadministering a first dose of an extended release dosage form of ARBACin the fed state, and b) orally administering a second dose of anextended release dosage form of ARBAC in the fasting state.

The positive food effect of the extended release dosage form of theinvention can be used to advantage by allowing administration of lowerdoses of ARBAC as compared to rac-BAC while providing substantially thesame or even improved clinical benefit. In some embodiments, theinvention provides a method of changing the current method of treatmentof a subject currently undergoing daily treatment with one or morerac-BAC daily doses to a second method of treatment, the methodcomprising: a) determining the current daily dose of rac-BAC in thesubject's current method of treatment; and b) if the subject iscurrently taking rac-BAC, indicating administration of a different doseof ARBAC in an extended release dosage form under fed conditions as thesecond method, wherein the different daily dose is less than the currentdaily dose. In some embodiments, the different daily dose is less than50 by wt % or mole %, on the basis of ARBAC, of the current daily dose.In some embodiments, the second method provides about the same clinicalbenefit as or provides an improved clinical benefit over the first(current) method. In some embodiments, the second method employs lessthan 50% of the dose of ARBAC as compared to the first (current) method.

In some embodiments, the subject's current method of treatment is ceasedbefore initiating the second method of treatment. In some embodiments,the subject's current method of treatment and the second method oftreatment according to the invention overlap. In some embodiments, thesubject's current method of treatment comprises oral, intrathecal,intravenous, intramuscular or intraperitoneal administration of ARBAC orrac-BAC. In some embodiments, the current method of treatment employsimmediate release oral dosage forms.

The invention also provides a method of increasing the concentration ofARBAC in the cerebrospinal spinal fluid (CSF) of a subject, the methodcomprising: a) administering a first total daily dose of ARBAC orrac-BAC to the subject for a period of at least two days sufficient toachieve at least a minimum therapeutically effective concentration ofARBAC in the CSF for a period of at least 12, at least 16 hours, atleast 20 hours or at least 24 hours after administration within a24-hour dosing period; and b) chronically orally administering secondtotal daily doses of ARBAC in an extended or controlled release dosageform to the subject throughout a treatment period sufficient to maintainthe at least minimum therapeutically effective concentration of ARBAC inthe CSF for a period of at least 16 hours, at least 20 hours or at least24 hours on a steady state basis within a 24-hour dosing period.

The invention includes embodiments, wherein: a) the first total dailydose is higher than the second total daily dose; b) the first totaldaily dose is lower than the second total daily dose; c) the minimumtherapeutically effective concentration of ARBAC in the CSF is at leastabout 2, at least about 3 or at least about 4 ng/ml when a total dailydose of 20 mg of ARBAC or a total daily dose of rac-BAC is administered;d) the minimum therapeutically effective concentration of ARBAC in theCSF is at least about 3, at least about 4 or at least about 5 ng/ml whena total daily dose of 30 mg of ARBAC or a total daily dose of rac-BAC isadministered; and/or e) the minimum therapeutically effectiveconcentration of ARBAC in the CSF is at least about 5, at least about 6or at least about 7 ng/ml when a total daily dose of 40 mg of ARBAC or atotal daily dose of rac-BAC is administered.

In some embodiments, the extended or controlled release dosage form ofthe invention provides a Cmax and AUC for ARBAC that is lower than thatprovided by an immediate release dosage form comprising rac-BAC but thesame molar amount of (R)-BAC and still provides substantially the sameor an improved clinical benefit over the immediate release dosage form.

In some embodiments, the extended or controlled release dosage form ofthe invention provides a lower Cmax and about the same AUC for ARBAC asthat provided by an immediate release dosage form comprising rac-BAC butthe same molar amount of (R)-BAC and still provides substantially thesame or an improved clinical benefit over the immediate release dosageform.

The invention provides a method of treating spasticity in a subjecthaving multiple sclerosis comprising orally administering one or moreAERT's, wherein the AERT is at least as therapeutically effective as butwith less adverse events than treatment with rapid release tabletsracemic baclofen on an equimolar basis of arbaclofen. The AERT of theinvention provides reduced adverse events than immediate release tableton an equimolar arbaclofen basis.

The invention provides a method of treating a condition that istherapeutically responsive to arbaclofen comprising orally administeringone or more AERT's to a subject in need thereof, wherein the methodprovides reduced adverse events associated with baclofen therapy. Theinvention also provides use of AERT's for the treatment of a conditionthat is therapeutically responsive to arbaclofen comprisingadministering one or more AERT's as described herein to a subject inneed thereof according to a dosing regimen as described herein.

The dosage form of the invention is administered orally once, twice orthree-times daily, including daytime and/or nighttime administration.

In some embodiments, the dosage form of the invention releases a majorof arbaclofen downstream of the stomach and upstream of the colon.

The invention includes all combinations of the aspects, embodiments andsub-embodiments disclosed herein. Other features, advantages andembodiments of the invention will become apparent to those skilled inthe art by the following description, accompanying examples and appendedclaims.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are part of the present specification and areincluded to further demonstrate certain aspects of the invention. Theinvention may be better understood by reference to one or more of thesedrawings in combination with the detailed description of the specificembodiments presented herein.

FIG. 1 depicts exemplary in vitro release profiles (max: squares;median: diamonds; min: triangles) for the controlled release deviceaccording to Example 1.

FIG. 2 depicts plasma exemplary profiles following oral administrationof a controlled release device according to Example 1 (containing 20 mgof ARBAC) to subjects under fed (squares) and fasting conditions(diamonds).

FIGS. 3 and 4A-4B depict sectional side views of exemplary controlledrelease dosage forms according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

By “environment” is meant an “environment of use”, which is a locale inwhich a device of the invention is placed and into which the contents ofthe device (dosage form) are released. By “aqueous environment of use”is meant an environment of use containing an aqueous medium to which adevice of the invention is exposed during use. The aqueous medium can bewater, buffer, aqueous fluid, body fluid or other such medium. Exemplaryaqueous environments of use include a subject, an assay fluid, or othersimilar environments. A subject can be human or non-human.

By “rapid release” is meant a release of an active agent to anenvironment over a period of 1-59 minutes or 1 minute to three hoursonce release has begun and release can begin within a few minutes afteradministration or after expiration of a delay period (lag time) afteradministration.

By “immediate release” is meant a release of an active agent to anenvironment over a period of seconds to no more than about 30 minutesonce release has begun and release begins within a second to no morethan about 15 minutes after administration. An immediate release dosageform is considered a more narrowly defined rapid release dosage form, sothe terms may be used interchangeably herein.

By “controlled release” is meant a release of an active agent to anenvironment over a period of about eight hours up to about 12 hours, upto about 14 hours, up to about 16 hours, up to about 18 hours, up toabout 20 hours, a day, or more than a day. The terms controlled release,sustained release and extended release are used interchangeably herein.A controlled release can also mean substantially continuous release ofdrug throughout the majority of the transit time of the dosage formthrough the gastrointestinal tract following oral administrationthereof.

A controlled release can begin within a few minutes after administrationor after expiration of a delay period (lag time) after administration.

A delayed but controlled release dosage form is one that provides adelayed release of a drug followed by a controlled release of the drug.By delayed release is meant any formulation technique wherein release ofthe active substance from the dosage form is modified to occur at alater time than that from a conventional immediate release product. Inother words, the beginning of the controlled release of drug is delayedby an initial period of time. The period of delay is generally about 5minutes to 10 hours, 30 minutes to 10 hours, 15 min to 5 hours, 15 minto 2 hours, 15 min to 1 hour, or 1 hour to 10 hours.

A zero-order release profile characterizes the release profile of adosage form that releases a constant amount of drug per unit time. Apseudo-zero order release profile is one that approximates a zero-orderrelease profile. A dissolution curve shows a zero or pseudo-zero orderrelease profile if its release rate remains constant (or relativelyconstant within ±10% of the average value) in the interval of time0≦a<t≦b. Any profile following the equation:

(M(t)/M _(r))=k(t−a)^(n)0.9≦n≦1.1

has the following release rate equation:

(1/M)(dM/dt)=kn(t−a)^(n-1)

A first order release profile characterizes the release profile of adosage form that releases a percentage of a drug charge per unit time. Apseudo-first order release profile is one that approximates a firstorder release profile. A dissolution curve shows a first or pseudo-firstorder release profile within a certain interval of time 0≦a<t≦b if itsrelease rate is a continued monotone decreasing function of time.Specifically, a dissolution curve shows a first order profile wheneverits release rate is proportional to the remaining undissolved amount ofdrug, as determined by the following equation:

(M(t)/MT)=1−exp(−kt)

A dissolution curve shows a pseudo-first order profile when the drugrelease rate decreases with time as described by the Fickian oranomalous Fickian diffusion controlled release equation:

(M(t)/M _(T))=kt ^(n), 0.3≦n≦0.7

In some embodiments, the invention excludes dosage forms that exhibit azero order or first order release profile.

A sigmoidal release profile characterizes the release profile of adosage form that releases a drug in a controlled manner but very slowlyduring a first release period, then more rapidly during a second releaseperiod and finally very slowly during a third release period such thatthe release profile resembles a sigmoid. A dissolution curve shows asigmoid release profile within a certain interval of time 0≦a<t≦b if itsrelease rate reaches a single maximum within the interval (a, b)excluding the extremes. That is equivalent to consider a point of timeT* so that the release rate is an increasing function of time for a≦t<T*and a decreasing function of time, as determined by the followingequation:

(M(t)/M _(T))=W _(inf){1−exp{−[(t−t _(i))/β]^(α)}}  Weibull Function

Parameter ranges:t₁: between 0 and 3β: between 7 and 12α: 1<α<3Winf: between 0.5 and 1.1

The core comprises at least one and preferably at least two waterswellable excipients which expand in size during use of the dosage form.A gel or gelatinous mass forms in the core when exposed to water. Drugis extruded from the core in the form of a gel via the preformedpassageway and/or the passageway formed by rupture. The drug diffusesfrom the gel in dissolved form during use.

In some embodiments, the dosage form exhibits a sigmoidal drug release(dissolution) profile. A sigmoidal release profile can be divided intothree phases: a first slower release rate phase, a second faster releaserate phase and a third slower release rate phase. An exemplary releaseprofile can be characterized as follows and as depicted in FIG. 1.

TABLE 1 Dissolution (% wt) Time Median or (hr) mean Max Min 0 0 0 0 2 1120 5 4 35 50 20 6 61 80 40 8 78 100 55 12 88 70

TABLE 2 Dissolution (% wt) Time Median or (hr) mean Max Min 0 0 0 0 2 1120 5 4 35 50 25 6 61 80 45 8 78 100 65 12 88 80

TABLE 3 Dissolution (% wt) Time Median or (hr) mean Max Min 0 0 0 0 2 1220 5 4 40 50 30 6 65 80 50 8 85 100 70 12 95 90

TABLE 4 Dissolution (% wt) Time Median or (hr) mean Max Min 0 0 0 0 2 1220 5 4 42 50 35 6 67 80 55 8 87 100 75 12 97 100

TABLE 5 Dissolution (% wt) Time Median or (hr) mean Max Min 0 0 0 0 1 1115 5 2 20 30 11 4 50 72 35 6 80 100 61 8 100 78

TABLE 6 Dissolution (% wt) Time Median or (hr) mean Max Min 0 0 0 0 1 710 2 2 15 20 7 4 40 50 25 6 65 85 50 8 85 100 70 10 100

The values set forth in the above tables and herein are approximatenumbers. Depending upon the conditions of measurement as well as theassay used to determine those values, they may have a standard deviationof +/−2%, +/−5% or +/−10% of the indicated value.

The maximum and minimum release profiles can be thought of asapproximations of the upper and lower boundaries within which therelease profile of the exemplary osmotic device will vary on an overallor point to point basis. In other words, the area defined by the upperand lower boundaries is an approximation of the mean release profileplus or minus the standard deviation at the points of measurement. Othermethods of forming an edge or seam on the surface of the osmotic devicebefore application of the film-forming material are considered withinthe scope of the invention.

The dosage form of the invention can provide a release profile whereinabout 40 to about 100% wt of the drug is released in a controlled orcontinuous manner over a period of about 6 to about 16 hours, about 6 toabout 14 hours, about 6 to about 12 hours, about 6 to about 10 hours,about 6 to about 9 hours, about 6 to about 8 hours, about 7 to about 14hours, about 8 to about 14 hours, or about 10 to about 14 hours afterplacement in an environment of use or after oral administration.

The release can be such that about 40 to about 80% wt of the drug isreleased by about six hours, about 55 to about 100% of the drug isreleased by about 8 hours, and no less than 70% of the drug is releasedby about 12 hours after placement in an environment of use or after oraladministration.

The release can be such that about 50 to about 100% wt of the drug isreleased by about six hours, about 65 to about 100% of the drug isreleased by about 8 hours, and no less than 90% of the drug is releasedby about 12 hours after placement in an environment of use or after oraladministration.

The release can be such that about 60 to about 100% wt of the drug isreleased by about six hours, about 75 to about 100% of the drug isreleased by about 8 hours, and no less than 90% of the drug is releasedby about 10 hours after placement in an environment of use or after oraladministration.

The release can also be such that about 45 to about 85% wt of the drugis released by six hours, about 65 to about 100% of the drug is releasedby 8 hours, and no less than 75% of the drug is released by 12 hours.The release can also be such that about 50 to about 85% wt of the drugis released by six hours, about 70 to about 100% of the drug is releasedby 8 hours, and no less than 85% of the drug is released by 10 hours.The release can also be such that about 5 to about 40% wt of the drug isreleased by 2 hours, 45 to about 85% wt of the drug is released by sixhours, about 65 to about 100% of the drug is released by 8 hours, and noless than 75% of the drug is released by 12 hours.

The release can also be such that about 10 to about 20% wt of the drugis released by 2 hours, about 25 to about 50% is released by 4 hours,about 60 to about 90% wt of the drug is released by 8 hours, and no lessthan 75% of the drug is released by 12 hours. The release can also besuch that about 10 to about 20% wt of the drug is released by 2 hours,about 25 to about 50% is released by 4 hours, 60 to about 90% wt of thedrug is released by 8 hours, and no less than 80% of the drug isreleased by 12 hours. The release can also be such that about 7 to about20% wt of the drug is released by 2 hours, about 25 to about 45% isreleased by 4 hours, about 55 to about 80% wt of the drug is released by6 hours, and no less than 70% of the drug is released by 8 hours.

The release can also be such that no more than about 20% wt of the drugis released by 2 hours, about 20 to about 45% is released by 4 hours,about 55 to about 90% wt of the drug is released by 8 hours, and no lessthan 80% of the drug is released by 12 hours. The release can also besuch that no more than about 20% wt of the drug is released by 2 hours,about 30 to about 60% is released by 4 hours, about 50 to about 70% wtof the drug is released by 6 hours, no less than 70% of the drug isreleased by 8 hours and no less than 80% of the drug is released by 12hours. The release can also be such that no more than about 10% of thedrug is released by 1 hour, no more than about 20% wt of the drug isreleased by 2 hours, about 30 to about 50% is released by 4 hours, about40 to about 70% wt of the drug is released by 6 hours, no less than 60%of the drug is released by 8 hours and no less than 75% of the drug isreleased by 12 hours. The release can also be such that no more thanabout 10% of the drug is released by 1 hour, no more than about 20% wtof the drug is released by 2 hours, about 30 to about 50% is released by4 hours, about 40 to about 70% wt of the drug is released by 6 hours,about 60% to about 85% of the drug is released by 8 hours and no lessthan 75% of the drug is released by 12 hours.

In some embodiments, the release profile is sigmoidal. In someembodiments, the release profile is first order or zero order. Drug isreleased in a continuous or controlled manner. In some embodiments, thedosage form of the invention excludes a gastroretentive dosage form.

The three phases of a sigmoidal release profile can be divided accordingto the weight percentage of drug, in a dosage form, that is releasedduring each phase. In some embodiments, about 5-20% wt is releasedduring the first phase, about 45-70% wt is release during the secondphase and about 10-50% wt is released during the third phase. In someembodiments, about 5-15% wt is released during the first phase, about55-70% wt is release during the second phase and about 15-45% wt isreleased during the third phase. In some embodiments, about 5-15% wt isreleased during the first phase, about 50-70% wt is release during thesecond phase and about 25-35% wt is released during the third phase. Insome embodiments, the first phase lasts about 1 to 2 hours, the secondphase lasts about 4 to 8 hours, and the third phase lasts about 2 hoursor more. In some embodiments, the first phase lasts no more than about 2hours, the second phase lasts about 4 to 8 hours, and the third phaselasts about 2 hours or more. In some embodiments, the first phase lastsno more than about 3 hours, the second phase lasts about 3 to 6 hours,and the third phase lasts about 1 hour or more. In some embodiments, thefirst phase lasts no more than about 2 hours, the second phase lastsabout 3 to 6 hours, and the third phase lasts about 1 hour or more. Insome embodiments, the first phase lasts no more than about 2 hours, thesecond phase lasts about 3 to 5 hours, and the third phase lasts about 1hour or more.

The osmotic device provides an improved plasma profile (FIG. 2) whenorally administered to a subject as compared to other related osmoticdevices. The device unexpectedly exhibits a dramatic positive foodeffect contrary to the published literature on baclofen, which does notindicate the existence of a food effect upon the pharmacokineticparameters of baclofen when administered orally. The device was orallyadministered in the fed and fasting states according to Example 4. Itwas determined that the instant osmotic device provides a substantialincrease in Cmax, AUC_(0-t) and AUC_(0-inf) when administered in the fedstate as compared to the fasting state. The table below summarizes theresults for administration of an osmotic device containing 20 mg ofARBAC after a single dose.

TABLE 7 Mean values Parameter Fed Fasting Tmax (hr) about 5 (4-6) about4.5 (3.5-5.5) Cmax (ng/ml) about 155 (110-190) about 120 (80-150)AUC_(0-t) (ng · h/ml) about 1470 (1400-1900) about 800 (550-1080)AUC_(0-inf) (ng · h/ml) about 1490 (1400-1900) about 830 (550-1080)

Cmax increases by about 25-30%, AUC_(0-t) increases by about 75-85% orabout 80%, AUC_(0-inf) increases by about 70-80% or about 75%, and Tmaxincreases by about 0.25 to about 0.75 hr or about 0.5 hr for the fedstate administration over the fasting state administration.

The food effect continues to exist even after chronic dosing asdemonstrated by steady state pharmacokinetics.

TABLE 8 Mean values Parameter Fed Fasting Tmax_(ss) (hr) about 5 (4-6)about 4.5 (3.5-5.5) Cmax_(ss) (ng/ml) about 170 (120-220) about 130(80-150) Cmin_(ss) (ng/ml) about 55 (10-100) about 40 (5-80) AUC_(ss)(ng · h/ml) about 1250 (1000-1700) about 890 (600-1150)

In another trial, the pharmacokinetic performance of the osmotic devicewas compared to that of an immediate release tablet of the same dosagestrength when orally administered in the fasting state and steady-statemultiple doses according to Example 5. It was determined that theinstant osmotic device provides a substantial decrease in Cmax andAUC₀₋₁₂ and a substantial increase in Tmax as compared to the IR tablet.The table below summarizes the results.

TABLE 9 Mean values Parameter Osmotic device (ARBAC) IR tablet (rac-BAC)Tmax (hr) (median about 4 about 1 or mean) Cmin (ng/ml) About 40 About90 Cavg (ng/ml) About 87 About 174 Cmax (ng/ml) about 160 about 336AUC₀₋₁₂ (ng · h/ml) about 1040 about 2080

The IR dosage form provides a higher Cmax and AUC than the osmoticdevice under fasting conditions and steady state following oraladministration of multiple doses.

In yet another trial, the pharmacokinetic performance of the osmoticdevice was compared to that of an immediate release tablet of the samedosage strength when orally administered in the fasting state and singledose according to Example 6. It was determined that the instant osmoticdevice provides a substantial decrease in Cmax and AUC₀₋₁₂ and asubstantial increase in Tmax as compared to the IR tablet. The tablebelow summarizes the results.

TABLE 10 Osmotic Osmotic Osmotic IR tablet device (10 device (15 device(20 (20 mg Parameter mg ARBAC) mg ARBAC) mg ARBAC) rac-BAC) Tmax (hr)about 5 about 4.5 About 5 about 1 (median or mean) Cmax (ng/ml) about 77about 100 About 142 about 425 AUC_(0-t) (ng.h/ml) about 555 about 680About 1060 about 2300 AUC_(0-inf) (ng · h/ About 575 About 700 About1090 About 2320 ml)

The IR dosage form provides a higher Cmax and AUC than the osmoticdevice under fasting conditions following oral administration of asingle dose.

In some embodiments, the ER dosage form provides a Tmax of about 4 toabout 7 hours, about 4 to about 5.5 hours, about 4 to about 5 hours,about 5 to about 7 hours or about 5 to about 6 hours after oraladministration.

The extended release dosage form of the invention can provide reducedside effects (adverse events) compared to rapid release tabletscontaining racemic baclofen on an equimolar basis of arbaclofen. Example7 details a study comparing the safety and efficacy of increasing dosesof arbaclofen extended release tablets (AERT) of the invention, placeboand rapid release tablets containing racemic baclofen. AERT (10, 15 or20 mg) are orally administered Q12h. Reference IR over-encapsulatedtablets of rac-BAC (10, 15 or 20 mg) are orally administered QID.Racemic baclofen is only 50% arbaclofen, so 10 mg of rac-baclofen isequal to 5 mg arbaclofen on a molar basis, and 10 mg of rac-baclofen QIDis equal to 10 mg of arbaclofen BID on a molar basis. Of 354 randomizedsubjects, 59.0% had relapsing remitting and 36.7% had secondaryprogressive MS. The average baseline TNmAS score was 7.78. TNmAS andCGIC were statistically significant in favor of AERT group compared withplacebo, while differences between AERT and baclofen were notstatistically significant. MS Spasticity Scale (MSSS-88) showed astatistically significant improvement in AERT group compared withplacebo. Epworth Sleepiness Scale (ESS) showed a statisticallysignificant increase in sleepiness in the baclofen group, but not in theAERT group compared to placebo. Drowsiness and dizziness were lessfrequent in AERT group compared with baclofen. Even though the AERTprovides substantially the same or better efficacy than the IR tablet,the AERT provides reduced sleepiness, drowsiness and/or dizziness.

The extended release (ER) dosage form exhibiting a positive food effectcan be used to advantage in changing the current treatment of a subjectundergoing rac-BAC or ARBAC therapy with other dosage forms notexhibiting a positive food effect. The subject's current treatment canbe changed by reducing the dose of ARBAC administered while providingsubstantially the same or an improved clinical benefit whenadministering the ER dosage form with food. The subject's currenttreatment can also be changed by maintaining the same dose of ARBACadministered while providing an improved clinical benefit whenadministering the ER dosage form with food.

It has been determined that the plasma concentration of ARBAC is lesscritical than the concentration of ARBAC in CSF when treatingspasticity, in particular spasticity associated with multiple sclerosis.The plasma concentration of ARBAC is substantially higher than the CSFconcentration of ARBAC following administration of an ER dosage form ofthe invention. In some embodiments, the plasma concentration is at least2-fold, at least 4-fold, at least 6-fold, at least 8-fold or at least10-fold higher than the CSF concentration.

The invention provides a method of increasing the concentration of ARBACin the CSF of a subject by administration of an ER dosage form of theinvention. The method has two phases: a) a first phase during which asubject's concentration of ARBAC in CSF is increased to at least aminimum therapeutically effective concentration for a period of at least12 hours or at least 16 hours; and b) a second phase during which asubject's concentration of ARBAC in CSF is maintained daily at or abovethe at least minimum therapeutically effective concentration for aperiod of at least 16 or at least 20 hours per day on a steady statebasis during a treatment period. The first phase (the escalation phase)typically lasts 2-30 days, 2-21 days, 2-14 days, 2-7 days, 2-5 days or2-3 days. The second phase (the maintenance phase) comprises themajority or the remainder of a subject's treatment period. As usedherein, a treatment period is a period of time comprising plural dosingperiods, and a dosing period is a period time from administration of onedose to administration of another. A treatment period is typicallymeasured in days, weeks, months or years; whereas a dosing period istypically measured in hours. For example, BID administration isequivalent to two dosing periods in one day (or equivalent to one dailydosing period) in order to provide a total daily dose of drug. In someembodiments, the dosage form is administered once daily or twice daily.

In some embodiments, the invention provides a method of increasing theconcentration of ARBAC in the cerebrospinal spinal fluid (CSF) of asubject, the method comprising: a) administering a first total dailydose of ARBAC or rac-BAC to the subject for a period of at least twodays sufficient to achieve at least a minimum therapeutically effectiveconcentration of ARBAC in the CSF for a period of at least 12 hoursafter administration; and b) chronically orally administering a secondtotal daily dose of ARBAC in an extended release dosage form to thesubject sufficient to maintain the at least minimum therapeuticallyeffective concentration of ARBAC in the CSF for a period of at least 16hours on a steady state basis.

The positive food effect can also be used to advantage when changing thecurrent treatment method (protocol) of a subject undergoing treatmentwith ARBAC or rac-BAC. Since the ER dosage form provides at least thesame clinical benefit at a substantially reduced dose of drug ascompared to an IR dosage form containing rac-BAC, it can be used toreduce the amount of drug required to treat the subject. The inventionprovides a method of changing the current method of treatment of asubject undergoing daily treatment with one or more rac-BAC daily dosesto a second method of treatment, the method comprising: a) determiningthe current daily dose of rac-BAC in the subject's current method oftreatment; and b) indicating administration of a different dose of ARBACin an extended release dosage form under fed conditions as the secondmethod, wherein the different daily dose is less than the current dailydose. In its simplest embodiment, the invention can comprise merelysubstituting a subject's current IR dosage form of rac-BAC with an ERdosage of the invention comprising the same or a lower amount of ARBACon a molar basis. In some embodiments, the subject's second method willinclude oral administration of the ER dosage form in the fed state.

The food effect can also be used to advantage to further control theabsorption of ARBAC. For example, a subject can be orally administered adose under fasting conditions and later a dose under fed conditions in asingle day, or vice versa. For example, a subject could be administeredthe first dose with food and a second dose about 8 to 16 hours later.Fasting conditions are established by abstaining from consumption offood for at least 2, at least 3 or at least 4 hours beforeadministration of a dose. The first and second doses and/or dosage formscan be the same or different. One or both dosage forms will exhibit asubstantial positive food effect.

It is known that renally impaired subjects will typically experiencedrug accumulation, thereby causing higher Cmax and AUC values ascompared to subjects with healthy renal functions. Accordingly, thedoses described herein can be reduced further as needed for patientswith impaired renal function. The level of dose reduction can bedetermined by a supervising clinician according to the subject's extentof renal impairment. Typically, the greater the impairment, the lowerthe dose required to provide therapeutically effective plasma levels ofdrug.

By “unitary core” is meant the core of an osmotic device that is notdivided into two or more layers or laminas. The core is considered to bethe composition enclosed within the wall, e.g. semipermeable membrane,of the osmotic device. The ingredients of the core may be present as aheterogeneous mixture or homogeneous mixture. A homogeneous mixture isone wherein all of the ingredients have been thoroughly mixed such thatthe composition of the formulation is substantially the same throughoutdifferent portions of the core. The combined step of mixing and directlycompressing the ingredients of the core generally provides a homogeneousmixture. A heterogeneous mixture is one wherein the ingredients of thecore are divided into two or more groups that are processed separatelyto form two or more respective blends, at least one of which containsdrug and at least one of which contains the osmagent. The blends arethen mixed together and compressed to form the unitary core. Aheterogeneous mixture can be obtained by wet granulation, drygranulation, pelleting or combinations thereof. In some embodiments, wetgranulation is preferred.

The terms “osmotic device” and “controlled release” or “extendedrelease” dosage form are generally used herein interchangeably. Anosmotic device is a controlled release device that comprises asemipermeable membrane surrounding the compressed drug-containing core,and optionally one or more other coatings and/or membranes. Thepreformed passageway is disposed at least through the semipermeablemembrane.

The osmotic device can also comprise an inert water soluble or erodiblecoat composition surrounding the semipermeable membrane. The preformedpassageway can be disposed through the inert water soluble or erodiblecoat composition and the semipermeable membrane or just through thesemipermeable membrane.

FIG. 3 depicts a controlled release device (1) according to Example 1.The device comprises a core (2) surrounded by a semipermeable membrane(3) which includes a preformed passageway (4). Drug and osmopolymer(typically in gel form) exit through the passageway when the device isexposed to an aqueous environment of use. The device optionallycomprises a drug-containing coat (5) exterior to the membrane (3). Ifthe coat is placed onto the membrane after the preformed passageway hasbeen formed in the membrane, then the coat plugs the passageway.

As used herein, the term “rupture” refers to breakage of the membranesuch as by bursting, splitting, cracking, rending, severing, fracturing,tearing, cleaving, forcing open, puncturing, splitting, or ripping. Therupture occurs only to the extent that drug is still released from thecore in a controlled release after rupture of the membrane. Ruptureaccording to the invention excludes embodiments wherein the membranebreaks catastrophically thereby releasing the entire contents of thecore in a burst or rapid manner. The mechanism of rupture, as usedherein, is distinguished from mechanisms such as leaching, erosion ordissolution of material from the membrane, e.g. by inclusion of apore-former in the membrane. The invention includes embodiments whereinthe membrane ruptures even though it may also include a pore former.

One or more weakened regions can be included in the semipermeablemembrane by: etching or scoring the membrane; shaping the osmotic devicesuch that it has a shoulder, ridge, or border covered by the membraneand the membrane thickness at the shoulder, ridge or border is thinnerthan at a face adjacent the shoulder, ridge or border; including abrittling agent at one or more locations within or throughout themembrane; and/or applying the semipermeable membrane unevenly to thecore or subcoat such that the membrane comprises one or more regions(weakened regions) that are thinner than the rest of the membrane, i.e.the membrane has a non-uniform thickness. One or more weakened regionscan be independently located adjacent or spaced away from one or morepreformed passageways. The membrane may comprise one or two preformedpassageways and one or two weakened regions. The membrane will compriseat least one preformed passageway and at least one weakened region.

The present inventors have developed a process for forming weakenedsection(s) at one or more specific locations of a corresponding osmoticdevice. In some embodiments, the shape of the tablet includes one ormore edges or shoulders or seams that create a weakened section themembrane during the film-forming process. The osmotic device (1) of FIG.3 comprises two convex faces (made with concave punch; 6)circumferentially attached to a middle cylindrical section (7). Edges orshoulders (8) are formed at the areas where the faces (6) andcylindrical side (7) meet. The edges/shoulders comprise weakenedsections, because the film formed at those locations is structurallycompromised. FIG. 4A depicts an osmotic device (10) with flat faces(made with flat face punch), and FIG. 4B depicts an osmotic device (11)with concave faces (made with convex punch). As a result, increase ininternal osmotic pressure ultimately causes rupture of one or morelocations of the edges; however, it is necessary that the core compriseat least one water swellable excipient. Greater reproducibility and lessvariability is observed in the dissolution and plasma profiles of abatch of osmotic devices as compared to a batch of otherwise similarosmotic devices not having one or more edges, shoulders or seams. Othermethods of forming an edge or seam on the surface of the osmotic devicebefore application of the film-forming material are considered withinthe scope of the invention. In some embodiments, the shape of the tabletcan be an ellipsoid of revolution or spheroid such that it does notcomprise an edge or shoulder. The invention includes embodiments whereinthe membrane does not rupture during use and embodiments wherein themembrane ruptures during use.

The examples disclose controlled release device formulations that differin the composition of the core and semipermeable membrane.

The release profile of the osmotic device of the invention may vary fromthat shown in FIG. 1 according to the materials used to form the coreand the semipermeable membrane covering the core, as well as the methodused to form the passageway. For example, the release profile can beinfluenced by the various alternate embodiments of the preformedpassageway such as the different sizes, shapes and functions. Therelease profile can also be influenced by the amount and properties ofthe active agent used to form the core, the amount of excipient used toform the core, the type of excipient used to form the core, and theamount or type of any other material used to form the core such asosmotically effective solutes, osmopolymers, or osmagents. The releaseprofile can also be influenced by the material used to form thesemipermeable membrane, covering the subcoat or by the material used toform any coating on the semipermeable membrane.

It should be understood that the device can assume any shape or formcurrently known in the art of osmotic devices. That is, the device mayassume any different shape and/or size according to which are optimalfor the intended environment of use. In some embodiments, its compressedcore will comprise one or more shoulders, ridges or edges covered by themembrane. In particular embodiments, the shape and size of the devicewill be optimal for use in subject mammals such as animals or humanbeings. The device can also include surface markings, cuttings, grooves,letters and/or numerals for the purposes of decoration, identificationand/or other purposes.

Osmotically effective solutes or osmotic agents, i.e. osmagents, thatare capable of being totally or partially solubilized in the fluid, canbe included in the core. These osmagents will aid in either thesuspension or dissolution of the active agent in the core. Exemplaryosmagents include organic and inorganic compounds such as salt, acid,base, chelating agent, halide salt, sodium chloride, lithium chloride,magnesium chloride, magnesium sulfate, lithium sulfate, potassiumchloride, sodium sulfite, calcium bicarbonate, sodium sulfate, calciumsulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose,sucrose, alpha-d-lactose monohydrate, glucose, combinations thereof andother similar or equivalent materials which are widely known in the art.In some embodiments a halide salt is preferred.

These osmagents can also be incorporated to the core of the osmoticdevice to control the release of an active agent therein.

One or more osmopolymers (water swellable excipient(s), water swellableagent(s), water swellable polymer(s)) can also be added to the core ofthe device to aid in the delivery of the active agents. A “swellableagent” is any material that increases its volume upon exposure to asolution, such as a polymeric sorbent, for example, sodium polyacrylate,sodium polyacrylamide, poly-N-vinylpyrrolidone,poly-vinyltoluenesulfonate, poly-sulfoethyl acrylate,poly-2-hydroxyethyl acrylate, poly-vinylmethyloxazolidinone, hydrolyzedpolyacrylamide, polyacrylic acid, copolymers of acrylamide and acrylicacid, and alkali metal salts of such of the polymers as containsulfonate or carboxylate groups (see U.S. Pat. No. 3,926,891; U.S. Pat.No. 3,699,103, U.S. Pat. No. 5,693,411, all herein incorporated byreference in their entirety), or a naturally occurring water-swellableagent, such as mangrot seed, ground root of the buuk plant, cotton andsponge.

Osmopolymers are well known to those of ordinary skill in the osmoticdevice art and well described in the patent and scientific literature.Exemplary osmopolymers include hydrophilic polymers that swell uponcontact with water. Osmopolymers may be of plant or animal origin, orsynthetic. Examples of osmopolymers include: poly(hydroxy-alkylmethacrylates) with molecular weight of 30,000 to 5,000,000,poly(vinylpyrrolidone) with molecular weight of 10,000 to 360,000,anionic and cationic hydrogels, polyelectrolyte complexes, poly(vinylalcohol) having low acetate residual, optionally cross-linked withglyoxal, formaldehyde or glutaraldehyde and having a degree ofpolymerization of 200 to 30,000, a mixture of methyl cellulose,cross-linked agar and carboxymethylcellulose, a mixture of hydroxypropylmethylcellulose and sodium carboxymethylcellulose, sodiumcarboxymethylcellulose, hydroxypropyl methylcellulose, polyethyleneoxide, polymers of N-vinyllactams, polyoxyethylene-polyoxypropylenegels, polyoxybutylene-polyethylene block copolymer gels, carob gum,polyacrylic gels, polyester gels, polyurea gels, polyether gels,polyamide gels, polypeptide gels, polyamino acid gels, polycellulosicgels, carbopol acidic carboxy polymers having molecular weights of250,000 to 4,000,000, Cyanamer polyacrylamides, cross-linkedindene-maleic anhydride polymers, Good-Rite™ polyacrylic acids havingmolecular weights of 80,000 to 200,000, polyalkylene oxide (PAO)polymers, Polyox™ polyethylene oxide (PEO, which is a PAO) polymershaving molecular weights of 100,000 to 5,000,000, starch graftcopolymers, and Aqua-Keeps™ acrylate polymer polysaccharides.

In some embodiments, the core comprises two different water swellablepolymers, wherein one polymer is present as a major portion and theother polymer is present as a minor portion of the total amount of waterswellable polymer present. In some embodiments, the core comprisespolyalkylene oxide (PAO) and hydroxyalkylcellulose derivative. In someembodiments, the PAO is present in a greater amount than thehydroxyalkylcellulose derivative. In some embodiments, the corecomprises PEO and HPMC. In some embodiments, the PEO is present in agreater amount than the HPMC. In some embodiments, the weight ratio ofPEO to HPMC in the core ranges from about 10:1 to about 25:1, about 12:1to about 22:1, about 14:1 to about 25:1, about 14:1 to about 21:1, about13:1 to about 17:1, about 15:1, about 17:1 to about 22:1, about 18:1 toabout 20:1, or about 19:1.

One or more grades of PEO can be used as the swellable polymer(s) in thecore. Suitable grades include are listed below.

Approx. Molecular Viscosity POLYOX Grades INCI Name Weight (cPs) POLYOXWSR N-10 PEG-2M 100,000 12-50a POLYOX WSR N-80 PEG-5M 200,000  65-115aPOLYOX WSR N-750 PEG-7M 300,000   600-1,000a POLYOX WSR N-3000 PEG-14M400,000 2250-4500a POLYOX WSR-205 PEG-14M 600,000 4500-8800a POLYOX WSRN-12K PEG-23M 1,000,000 400-800b POLYOX WSR N-60K PEG-45M 2,000,000200-400b POLYOX WSR-301 PEG-90M 4,000,000 1650-5500c

In some embodiments, the PEO has a molecular of: about 4,000,000 orless, about 3,000,000 or less, about 2,000,000 or less, about 1,000,000or less, about 1,000,000, about 600,000, about 400,000, about 300,000,about 200,000 or about 100,000. A combination of two or more grades ofPEO can be used.

These materials swell or expand to an equilibrium state when exposed towater or other biological fluids. This volume expansion is used tophysically force the pharmaceutical agent out through openings that havebeen formed in the wall, shell or coating during manufacture. A waterinsoluble or poorly water soluble active agent is primarily released asinsoluble particles, which therefore have limited bioavailability.Exemplary osmopolymers are disclosed in U.S. Pat. No. 5,422,123; No.4,783,337; No. 4,765,989; No. 4,612,008; No. 4,327,725; No. 4,609,374;No. 4,036,228; No. 4,992,278; No. 4,160,020; 4,615,698. The osmopolymersgenerally swell or expand to a very high degree, usually exhibiting a 2to 60 fold volume increase. The osmopolymers can be non-cross-linked orcross-linked. The swellable, hydrophilic polymers are, in someembodiments, lightly cross-linked, such as cross-links being formed bycovalent or ionic bonds.

In some embodiments, the core comprises at least one water swellablepolymer and at least one osmagent. These excipients can be present inweight ratios of about 1.5:1 to about 1:1.5, about 1.25:1 to about1:1.25, about 1.25:1 to about 1:1, about 1.2:1 to about 1:1, about1.1:1, about 0.7:1 to about 1:1, about 0.8:1 to about 1:1, about 0.85:1to about 0.95:1, or about 0.9:1 based upon the total amount of waterswellable polymer to the total amount of osmagent.

Many common materials known by those of ordinary skill in the art aresuitable for use as the semipermeable membrane. Exemplary materialsinclude cellulose esters, cellulose ethers, cellulose esters-ethers andcombinations thereof. However, it has been found that a semipermeablemembrane consisting essentially of cellulose acetate (CA) andpoly(ethylene glycol) (PEG). In some embodiments, PEG 400, is preferredwhen used in combination with CA. This particular combination of CA andPEG provides a semipermeable membrane that gives the osmotic device awell controlled release profile for the active agent in the core andthat retains its chemical and physical integrity in the environment ofuse. In some embodiments, the weight ratio of CA:PEG generally rangesfrom about 90-99% by weight of CA: about 10-1% by weight of PEG, andgenerally about 93-96% by weight of CA: about 7-4% by weight of PEG. Theratio can be varied to alter permeability and ultimately the releaseprofile of the osmotic device.

Representative materials for making the semipermeable membrane include amember selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono, di and tricellulose alkanylates,mono, di and tricellulose aroylates, and the like. Exemplary polymersinclude cellulose acetate having a D.S. up to 1 and an acetyl content upto 21%; cellulose acetate having an acetyl content of 32 to 39.8%;cellulose diacetate having a D.S. of 1 to 2 and an acetyl content of 21to 35%; cellulose triacetate having a degree of substitution (D.S.) of 2to 3 and an acetyl content of 35 to 44.8%; and the like. More specificcellulosic polymers include cellulose propionate having a D.S. of 1.8and a propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl contentof 13 to 15% and a butyryl content of 34 to 39%; cellulose acetatebutyrate having an acetyl content of 2 to 29%, a butyryl content of 17to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylateshaving a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulosetrilaurate, cellulose tripalmitate, cellulose trisuccinate, andcellulose trioclanoate; cellulose diacylates having a D.S. of 2.2 to 2.6such as cellulose disuccinate, cellulose dipalmitate, cellulosedioclanoate, cellulose dipentalate, and the like. Additionalsemipermeable polymers include acetaldehyde dimethyl acetate, celluloseacetate ethyl carbamate, cellulose acetate phthalate for use inenvironments having a low ph, cellulose acetate methyl carbamate,cellulose acetate dimethyl aminoacetate, semipermeable polyamides,semipermeable polyurethanes, semipermeable sulfonated polystyrenes,cross-linked selectively semipermeable polymers formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. No. 3,173,876, No. 3,276,586, No. 3,541,005, No. 3,541,006, and No.3,546,142; semipermeable polymers as disclosed by Loeb and Sourirajan inU.S. Pat. No. 3,133,132; lightly cross-linked polystyrene derivatives;cross-linked poly(sodium styrene sulfonate), cross-linkedpoly(vinylbenzyltrimethyl ammonium chloride). These and others polymersare disclosed in U.S. Pat. No. 3,845,770, No. 3,916,899, U.S. Pat. No.4,765,989 and U.S. Pat. No. 4,160,020; and in Handbook of CommonPolymers (Scott, J. R. and Roff, W. J., eds.; 1971; CRC Press,Cleveland, Ohio).

The cellulose esters differ in their cellulose chain length and the typeand amount of ester groups attached to the chain. For celluloseacetates, as the amount of acetyl content increases, the permeabilitydecreases. The cellulose acetate grade 3 comprises 7-10% by weight ofhydroxyl groups and has a viscosity of 200-280 seconds as determined byASTM Method D 1343. The cellulose acetate grade 4 comprises 3-5% byweight of hydroxyl groups and has a viscosity of 6 to 45 seconds. Thecellulose acetate grade 5 comprises 3-5% by weight of hydroxyl groupsand has a viscosity of 100 to 240 seconds.

Some exemplary grades of cellulose acetate that are suitable for use inthe making the semipermeable membrane are also described in the tablebelow, which is included by way of example. Cellulose acetate ofdiffering grades is readily available from Eastman Chemical Company(Kingsport, Tenn., USA).

Hydroxyl Content Acetyl Content Cellulose Acetate (% by wt.) (% by wt.)Viscosity* Grade 1 8.7 32 2.4 P Grade 2 3.5 39-40, 39.8  38 P Grade 3 7-10 30-36 200-280 sec* Grade 4 3-5 37-43   6-45 sec* Grade 5 3-5 37-43100-240 sec* *Viscosity determined as set forth in ASTM D817 (Formula A)and D1343, the disclosure of which is hereby incorporated by reference.

The above amounts are approximate (about) due to lot-to-lotmanufacturing variations. Grade 1 can be considered a more narrowlydefined Grade 3. Grade 2 can be considered a more narrowly defined Grade5.

In some embodiments, the semipermeable membrane comprises at least twofilm-forming cellulose ester polymers. The polymers can be of twodifferent grades but of the same type or of two different types. In someembodiments, the semipermeable membrane comprises a plasticizer and thefollowing two cellulose acetate (CA) polymers.

I II III IV V CA  5-10 mg  6-12 mg 20-50% wt 20-40% wt 40-60% wt Grade 1CA 10-25 mg 12-28 mg 80-50% wt 80-60% wt 60-40% wt Grade 2 VI VII VIIIXI X CA 0-35 mg 4-12 mg 100-60% wt 40-30% wt  0-40% Grade 1 CA 35-0 mg26-8 mg  0-40% wt 60-70% wt 100-60% Grade 2

The plasticizer can be present in the following amounts or percentages,based upon the weight of the final dried membrane: 0.1-5 mg, 0.1-4 mg,0.1-3 mg, 0.1-15% wt, 0.1-12.5% wt, 0.1-10% wt., 1-10% wt, 3 or −9% wt.or other ranges specified herein. The plasticizer can be PEG, esp. PEG400, or as otherwise specified herein.

Plasticizers can be included in the semipermeable membrane to modify theproperties and characteristics of the polymers used in the coats or coreof the device. As used herein, the term “plasticizer” includes allcompounds capable of plasticizing or softening a polymer or binder usedin invention. The plasticizer should be able to lower the meltingtemperature or glass transition temperature (softening pointtemperature) of the polymer or binder. Plasticizers, such as lowmolecular weight PEG, generally broaden the average molecular weight ofa polymer in which they are included thereby lowering its glasstransition temperature or softening point. Plasticizers also generallyreduce the viscosity of a polymer. It is possible the plasticizer willimpart some particularly advantageous physical properties to the osmoticdevice of the invention.

Plasticizers useful in the invention can include, by way of example andwithout limitation, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin. Such plasticizers can alsoinclude ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, diethylene glycol, triethylene glycol, tetraethyleneglycol and other poly(ethylene glycol) compounds, monopropylene glycolmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate and allyl glycolate. All such plasticizers arecommercially available from sources such as Aldrich or Sigma ChemicalCo. It is also contemplated and within the scope of the invention, thata combination of plasticizers may be used in the present formulation.The PEG based plasticizers are available commercially or can be made bya variety of methods, such as disclosed in Poly(ethylene glycol)Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.;Plenum Press, NY) the disclosure of which is hereby incorporated byreference.

The optional inert polymer coat that covers the semipermeable membraneis made of synthetic, semisynthetic or natural material which, throughselective dissolution and/or erosion shall allow the passageway to beunblocked thus allowing the process of osmotic delivery to start. Theinert polymer coat will generally comprise an inert and non-toxicmaterial which is at least partially, and generally substantiallycompletely, soluble and/or erodible in an environment of use.

An optional drug-containing coat exterior to the semipermeable membranemay contain a second active agent that may or may not be the same as afirst active agent in the core. The second active agent is available forimmediate release. The second active agent can be applied to the surfaceof the device according to common methods of preparing similar osmoticdevices such as applying to its surface solids in solution or suspensionthrough the use of a sprayer that spreads them uniformly over the coreor by employing nucleated compression or other suitable methods known tothose of ordinary skill in the art. The external coat can comprisepoly(vinylpyrrolidone) (PVP) and poly(ethylene glycol) (PEG) and canfurther comprise materials such as, by way of example and withoutlimitation, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose(HEC), sodium carboxymethyl-cellulose (CMC), dimethylaminoethylmethacrylate—methacrylic acid ester copolymer,ethylacrylate—methylmethacrylate copolymer (GA-MMA), C-5 or 60 SH-50(Shin-Etsu Chemical Corp.) and combinations thereof. The activeagent-containing external coat can also comprise dissolution aids,stability modifiers, and bioabsorption enhancers.

Those of ordinary skill in the art will appreciate that the particularamount of second active agent employed will vary according to, amongother things, the identity and physical properties and characteristicsof the second active agent, the intended application of the osmoticdevice, the desired effect the second active agent is intended to have,and the physiological condition, if any, being treated. In someembodiments, the osmotic device excludes a drug-containing coat exteriorto the semipermeable membrane.

As used herein, the term “preformed passageway” refers to a passagewayor passageway precursor that has been formed on the semipermeablemembrane of the device by mechanical means, such as by a laser, drilland/or etching apparatus. A preformed passageway is optionally pluggedafter initial formation, such as depicted in FIG. 3. The term “preformedpassageway” is not intended to cover pores, holes, apertures, channelsor other similar structures formed in the semipermeable membrane byincorporation of pore formers, water soluble particulates, or similarmaterials known to those of ordinary skill, into the semipermeablemembrane of the rupturing controlled release device during manufactureof the osmotic device.

The osmotic device of the invention comprises at least one preformedpassageway (pore, hole, or aperture) that communicates the exterior ofthe semipermeable membrane with the core of the device. The preformedpassageway can be formed according to any of the known methods offorming passageways in a semipermeable membrane. Such methods include,for example, 1) drilling a hole through the semipermeable membrane witha bit or laser; 2) punching a hole through the semipermeable membrane;or 3) employing a tablet punch having a pin to punch a hole through thesemipermeable membrane. The passageway can pass through thesemipermeable membrane and one or more of any other coating onto thesemipermeable membrane or between the semipermeable membrane and thecore. The passageway(s) can be shaped as desired. In some embodiments,the passageway is laser drilled and is shaped as an oval, ellipse, slot,slit, cross or circle.

Methods of forming preformed passageways in semipermeable membranes ofosmotic devices are disclosed in U.S. Pat. No. 4,088,864 to Theeuwes etal., U.S. Pat. No. 4,016,880 to Theeuwes et al., U.S. Pat. No. 3,916,899to Theeuwes et al., U.S. Pat. No. 4,285,987 to Ayer et al., U.S. Pat.No. 4,783,337 to Wong et al., U.S. Pat. No. 5,558,879 to Chen et al.,U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 3,845,770 toTheeuwes et al., PCT International Publication No. WO 04/103349 toFaour, and U.S. Pat. No. 6,809,288 to Faour, the disclosures of whichare hereby incorporated by reference.

A preformed passageway can be made to substantially retain its sizeduring use of the device or it can be made to increase in size duringuse of the dosage form. Preformed passageways of different sizes, shapesand functions can be used.

In some embodiments, the membrane defining the edge of the preformedpassageway in the wall may tear (rupture) in a predetermined or randommanner, and the shape of the preformed passageway after enlargement canbe made to approximate a predetermined or randomly determined shape. Theextent to which a passageway increases in size can also be related tothe viscosity, molecular weight or degree of substitution of the atleast one excipient. Generally, increasing the viscosity, molecularweight, or degree of substitution of the at least one excipient willincrease the extent to which the passageway increases in size. In someembodiments, the edge of the membrane defining the preformed passagewayin the wall does not tear during use of the osmotic device.

A device according to the present invention can comprise one or morepreformed passageways including two, three, four, five, six, seven,eight, nine, ten or more preformed passageways. It is only necessarythat the preformed passageways together are adapted to permit controlledrelease of ingredients from the core during use. In some embodiments,the semipermeable membrane comprises at least one preformed passagewayhaving a diameter ranging from about 0.2 to about 0.8 mm, about 0.2 toabout 0.6 mm, about 0.4 to about 0.8 mm, about 0.4 to about 0.6 mm,about 0.5 mm, about 0.7 mm, about 0.9 mm, about 1 mm. In otherembodiments, the total area of the preformed passageway(s) present inthe membrane ranges from 0.12 mm² to 2.1 mm². Preformed passageways ofdifferent sizes, shapes and functions can be employed.

The extent of rupture formation, i.e. the size of the rupture, can varyaccording to membrane thickness, membrane brittleness or flexibility,membrane composition, extent of swelling or expansion of the core duringuse, the thickness or weight of the subcoat. A thick membrane (0.3-1.5mm) will generally rupture to a lesser extent than a thin membrane(0.075-0.29 mm). A brittle membrane will generally rupture to a greaterextent than a flexible membrane. The more a core expands overall duringuse, the greater the extent of rupture overall. As the amount or weightof the subcoat increases, the overall or final rupture size decreases.After its initial formation in situ, the rupture can remain the samesize or can increase in size during use. The formation of the rupture isabrupt; however, its subsequent increase in size can be gradual orintermittent.

Membrane thickness is related to membrane weight, i.e. the final weightof the membrane after preparation. Generally, the thicker the membrane,the heavier it is and the slower the release rate of drug. In someembodiments, a membrane weighing from 15 mg to 35 mg is applied to acore weighing from 100 mg to 300 mg. In some embodiments, theapproximate membrane and core weights (based upon the weight of corewithout the membrane) are in any of the following ranges.

Weight Weight Weight Weight Weight Weight Element (mg) (mg) (mg) (mg)(mg) (mg) Core 100-150 110-140 150-220 170-200 200-300 225-275 Membrane15-30 17-23 20-35 22-27 or 20-35 22-27 or or or 22-31 22-31 22-29

The osmotic device of the invention can also comprise adsorbents,antioxidants, buffering agents, colorants, flavorants, tabletantiadherents, tablet binders, tablet diluents, tablet fillers, tabletdirect compression excipients, tablet glidants, tablet lubricants,tablet opaquants, colorant and/or tablet polishing agents.

As used herein, the term “adsorbent” is intended to mean an agentcapable of holding other molecules onto its surface by physical orchemical (chemisorption) means. Such compounds include, by way ofexample and without limitation, powdered and activated charcoal andother materials known to one of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene (BHT),hypophosphorous acid, monothioglycerol, propyl gallate, sodiumascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate and sodiummetabisulfite and other materials known to one of ordinary skill in theart.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon dilution or addition of acidor alkali. Such compounds include, by way of example and withoutlimitation, potassium metaphosphate, potassium phosphate, monobasicsodium acetate and sodium citrate anhydrous and dihydrate and othermaterials known to one of ordinary skill in the art.

As used herein, the term “tablet binders” is intended to mean substancesused to cause adhesion of powder particles in tablet granulations. Suchcompounds include, by way of example and without limitation, acacia,poly(vinylpyrrolidone), compressible sugar (e.g., NuTab™),ethylcellulose, gelatin, liquid glucose, povidone, copovidone (KOLLIDON®VA 64; BASF Group, Germany), pregelatinized starch, tragacanth, starch,cellulose materials such as methyl cellulose and sodium carboxy methylcellulose, alginic acids and salts thereof, polyethylene glycol, guargum, polysaccharide, bentonites, sugars, invert sugars, poloxamers(PLURONIC F68, PLURONIC F127), collagen, albumin, cellulosics innonaqueous solvents, combinations thereof and other materials known toone of ordinary skill in the art. Other binders include, for example,polypropylene glycol, polyoxyethylene-polypropylene copolymer,polyethylene ester, polyethylene sorbitan ester, polyethylene oxide,combinations thereof and other materials known to one of ordinary skillin the art.

KOLLIDON® VA 64 (copovidone) is a vinylpyrrolidone-vinyl. acetatecopolymer that is soluble in water and alcohol. The monomers are presentin an approximate molar ratio of 6:4. The copolymer has a molecularweight ranging from 45,000-70,000 as measured by laser light scatteringin solution. Additional information can be obtained from BASE(www.pharma-ingredients.basf.com) or “Kollidon—Polyvinylpyrrolidoneexcipients for the Pharmaceutical Industry (BASF leaflet 03_030743e).

In some embodiments, the core comprises copovidone as binder present inan amount ran from about 5% to about 15% wt, about 9% to about 13% wt,about 10 to about 12% wt or about 11% wt based upon the weight of theuncoated core. In some embodiments, the weight ratio of total waterswellable polymer to total binder in the core ranges from about 6:1 toabout 2:1, about 5:1 to about 3:1, about 4:1, about 5:1 to about 1:1,about 4:1 to about 1:1, about 3:1 to about 1:1, or about 2:1.

As used herein, the term “tablet antiadherents” is intended to meanagents which prevent the sticking of tablet formulation ingredients topunches and dies in a tableting machine during production. Suchcompounds include, by way of example and without limitation, magnesiumstearate, talc, calcium stearate, glyceryl behenate, PEG, hydrogenatedvegetable oil, mineral oil, stearic acid and other materials known toone of ordinary skill in the art.

As used herein, the term “tablet diluents” or “tablet fillers” isintended to mean inert substances used as fillers to create the desiredbulk, flow properties, and compression characteristics in thepreparation of tablets and capsules. Such compounds include, by way ofexample and without limitation, dibasic calcium phosphate, kaolin,lactose, sucrose, mannitol, microcrystalline cellulose (MCC), powderedcellulose, precipitated calcium carbonate, sorbitol, and starch andother materials known to one of ordinary skill in the art.

As used herein, the term “tablet direct compression excipient” isintended to mean a compound used in direct compression tabletformulations. Such compounds include, by way of example and withoutlimitation, dibasic calcium phosphate (e.g., Ditab) and other materialsknown to one of ordinary skill in the art.

As used herein, the term “tablet glidant” is intended to mean agentsused in tablet and capsule formulations to promote the flowability of agranulation. Such compounds include, by way of example and withoutlimitation, colloidal silica, cornstarch, talc, calcium silicate,magnesium silicate, colloidal silicon, silicon hydrogel and othermaterials known to one of ordinary skill in the art.

As used herein, the term “tablet lubricant” is intended to meansubstances used in tablet formulations to reduce friction during tabletcompression. Such compounds include, by way of example and withoutlimitation, calcium stearate, magnesium stearate, mineral oil, stearicacid, and zinc stearate and other materials known to one of ordinaryskill in the art.

As used herein, the term “tablet opaquant” is intended to mean acompound used to render a tablet coating opaque. It may be used alone orin combination with a colorant. Such compounds include, by way ofexample and without limitation, titanium dioxide and other materialsknown to one of ordinary skill in the art.

As used herein, the term “tablet polishing agent” is intended to mean acompound used to impart an attractive sheen to coated tablets. Suchcompounds include, by way of example and without limitation, carnaubawax, and white wax and other materials known to one of ordinary skill inthe art.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to solid (e.g., tablets) pharmaceutical preparations.Such compounds include, by way of example and without limitation, FD&CRed No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&CGreen No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide,red, other F.D. & C. dyes and natural coloring agents such as grape skinextract, beet red powder, beta-carotene, annato, carmine, turmeric,paprika, and other materials known to one of ordinary skill in the art.The amount of coloring agent used will vary as desired.

As used herein, the term “flavorant” is intended to mean a compound usedto impart a pleasant flavor and often odor to a pharmaceuticalpreparation. Exemplary flavoring agents or flavorants include syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may also include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaveoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Other useful flavors include vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavors which have been found to be particularly usefulinclude commercially available orange, grape, cherry and bubble gumflavors and mixtures thereof. The amount of flavoring may depend on anumber of factors, including the organoleptic effect desired. Flavorswill be present in any amount as desired by those of ordinary skill inthe art. Particularly preferred flavors are the grape and cherry flavorsand citrus flavors such as orange.

It is contemplated that the osmotic device of the invention can alsoinclude oils, for example, fixed oils, such as peanut oil, sesame oil,cottonseed oil, corn oil and olive oil; fatty acids, such as oleic acid,stearic acid and isotearic acid; and fatty acid esters, such as ethyloleate, isopropyl myristate, fatty acid glycerides and acetylated fattyacid glycerides. It can also be mixed with alcohols, such as ethanol,isopropanol, hexadecyl alcohol, glycerol and propylene glycol; withglycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol; withethers, such as poly(ethyleneglycol) 450, with petroleum hydrocarbons,such as mineral oil and petrolatum; with water, or with mixturesthereof; with or without the addition of a pharmaceutically suitablesurfactant, suspending agent or emulsifying agent.

Soaps and synthetic detergents may be employed as surfactants and asvehicles for detergent compositions. Suitable soaps include fatty acidalkali metal, ammonium, and triethanolamine salts. Suitable detergentsinclude cationic detergents, for example, dimethyl dialkyl ammoniumhalides, alkyl pyridinium halides, and alkylamine acetates; anionicdetergents, for example, alkyl, aryl and olefin sulfonates, alkyl,olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionicdetergents, for example, polysorbate, fatty amine oxides, fatty acidalkanolamides, and poly(oxyethylene)-block-poly(oxypropylene)copolymers, diethylene glycol monostearate, sodium lauryl sulfate,sorbitan monooleate, polyoxyethylene sorbitan fatty acid esters,polysorbate, bile salts, glyceryl monostearate, PLURONIC® line (BASF),and the like; and amphoteric detergents, for example, alkylaminopropionates and 2-alkylimidazoline quaternary ammonium salts; andmixtures thereof.

Various other components, not otherwise listed above, can be added tothe present formulation for optimization of a desired active agentrelease profile including, by way of example and without limitation,glycerylmonostearate, nylon, cellulose acetate butyrate, d,1-poly(lactic acid), 1,6-hexanediamine, diethylenetriamine, starches,derivatized starches, acetylated monoglycerides, gelatin coacervates,poly (styrene-maleic acid) copolymer, glycowax, castor wax, stearylalcohol, glycerol palmitostearate, poly(ethylene), poly(vinyl acetate),poly(vinyl chloride), 1,3-butylene-glycoldimethacrylate,ethyleneglycol-dimethacrylate and methacrylate hydrogels.

It should be understood, that compounds used in the art ofpharmaceutical formulations generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

Particular combinations of active agents that can be provided by thepresent controlled release device include: 1) a drug in the core from afirst therapeutic class and a different drug in the externaldrug-containing coat from the same therapeutic class; 2) a drug in thecore from a first therapeutic class and a different drug in the externaldrug-containing coat from a different therapeutic class; 3) a drug inthe core having a first type of biological activity and a different drugin the external drug-containing coat having about the same biologicalactivity; and/or 4) a drug in the core having a first type of biologicalactivity and a different drug in the external drug-containing coathaving a different second type of biological activity.

The therapeutic compound(s) contained within the present osmotic devicecan be formulated as its pharmaceutically acceptable salts. As usedherein, “pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the therapeutic compound is modified bymaking an acid or base salt thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and others known to those ofordinary skill. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known tothose of ordinary skill; and the salts prepared from organic acids suchas amino acids, acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and others known to those of ordinaryskill. The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent therapeutic compound which contains abasic or acidic moiety by conventional chemical methods. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosureof which is hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The amount of therapeutic compound incorporated in each device will beat least one or more unit dose and can be selected according to knownprinciples of pharmacy. An effective amount of therapeutic compound isspecifically contemplated. By the term “effective amount”, it isunderstood that, with respect to, for example, pharmaceuticals, apharmaceutically effective amount is contemplated. A pharmaceuticallyeffective amount is the amount or quantity of a drug or pharmaceuticallyactive substance which is sufficient to elicit the required or desiredtherapeutic response, or in other words, the amount which is sufficientto elicit an appreciable biological response when administered to apatient. In some embodiments, ARBAC is present at dose strength of about2.5 to about 50 mg, about 5 to about 15 mg, about 15 to about 25 mg,about 25 to about 50 mg, about 5 mg, about 10 mg, about 15 mg, about 20mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 7.5 toabout 12.5 mg, about 12.5 to about 17.5 mg, about 17.5 to about 22.5 mg,or about 22.5 to about 27.5 mg.

The term “unit dosage form” is used herein to mean a device containing aquantity of the drug, said quantity being such that one or morepredetermined units may be provided as a single therapeuticadministration.

If desired, the device of the invention can be coated with a finish coatas is commonly done in the art to provide the desired shine, color,taste or other aesthetic characteristics. Materials suitable forpreparing the finish coat are well known in the art and found in thedisclosures of many of the references cited and incorporated byreference herein. Printing may also be included in or on the dosageform.

The following examples should not be considered exhaustive, but merelyillustrative of only a few of the many embodiments contemplated by thepresent invention. The methods described herein can be followed toprepare and use dosage forms and methods according to the invention.

Example 1

The following procedure is used to prepare a controlled release devicecontaining GABA_(B) receptor agonist as active ingredient (low, mediumor high strength) in the core. The osmotic device tablets contain thefollowing ingredients in the amounts indicated:

Strength Strength Strength Ingredient L M H % wt % wt Core Active(mg) >5-13 13-17 17-25  4-12 8 Osmotic Agent 40-60 60-80  80-110 30-4536 (mg) Filler (mg) 4.5-7.5 7.5-10  10-15 3-7 4.6 Binder (mg) 10-1717-24 24-35  5-15 11 Swellable Polymer 1   2-3.1 3.1-4   4-8 0.1-5   2(mg) Swellable Polymer 2 40-60 60-80  80-110 30-45 38 (mg) Antioxidant(mg) 0.01-0.07 0.7-0.9 0.1- 0.01- 0.05 0.15 0.1 Glidant (mg) 0.2-0.30.3-0.4 0.4-0.7 0.01- 0.2 0.5 Lubricant (mg) 0.2-0.3 0.3-0.4 0.4-0.70.01- 0.2 0.5 Core weight 100-160 160-220 220-300 Semipermeable membraneRate film forming  5-10  6-12  6-12 20- 20-40% Polymer 1 (mg) 50% Ratefilm forming 10-25 12-28 12-28 80- 80-60% Polymer 2 (mg) 50% Plasticizer0.1-3   0.1-4   0.1-4   0.1- 01-10% Coating B (optional) Water soluble3-5 5-7 7-9 polymer with colorant

The core composition is prepared by placing active ingredient, twoosmopolymers, a diluent, an osmagent, and a binder in a high shear mixerand mix for 5 minutes. The granulation process is initiated by thegradual addition of a granulating solution containing a surfactant andpurified water to the high shear with continuous blending to produce awet blend. Next, the wet blend is granulated and dried at 40-50° C. for20 minutes in a fluid bed to remove the water. Then, the dry granulesare screened through a 30 USP mesh screen for size reduction. Next, thescreened granules are mixed with a glidant and a lubricant, that havebeen previously passed through a 60 mesh screen, in a V-Blender during 5minutes. This final blend is tableted to provide the cores. Tablettingcan be conducted using concave, convex or flat surface punches and dies.The compressed core can comprise one or more edges on the surface.

A first composition (semipermeable membrane) to cover the core isprepared as follows: two cellulose esters and a plasticizer are added toorganic solvent and purified water, and mixed thoroughly to form apolymer solution. This solution is sprayed onto the tablets in aperforated pan coater to form film-coated cores. The cores will compriseone or more weakened sections along one or more edges.

A 0.25-1.5 mm hole is drilled through the coating to provide perforatedfilm-coated tablets.

A finish coat (coating B) comprising Opadry and a colorant in purifiedwater is applied onto the film-coated tablets to obtain the osmoticdevice tablets.

Example 2

The procedure of Example 1 is followed to prepare a controlled releasedevice containing GABA_(B) receptor agonist as active ingredient (low,medium or high strength) in the core. The osmotic device tablets containthe following ingredients in the amounts indicated:

Strength Strength Strength Ingredient 10 mg 15 mg 20 mg % wt Core Active(mg) About 10 About 15 About 20 4-12 Osmotic Agent (mg) 40-60 60-8080-110 30-45 Filler (mg) 4.5-7.5 7.5-10  10-15 3-7 Binder (mg) 10-1717-24 24-35  5-15 Swellable Polymer 1   2-3.1 3.1-4   4-8 0.1-5   (mg)Swellable Polymer 2 40-60 60-80  80-110 30-45 (mg) Antioxidant (mg)0.01-0.07 0.7-0.9  0.1-0.15 0.01-0.1  Glidant (mg) 0.2-0.3 0.3-0.40.4-0.7 0.01-0.5  Lubricant (mg) 0.2-0.3 0.3-0.4 0.4-0.7 0.01-0.5  Coreweight 100-160 160-220 220-300 Semipermeable membrane Rate film forming 5-10  6-12  6-12 20-45% Polymer 1 (mg) Rate film forming 10-25 12-2812-28 75-55% Polymer 2 (mg) Plasticizer 0.1-3   0.1-4   0.1-4   0.1- 10%Coating B (optional) Water soluble polymer 3-5 5-7 7-9 with colorant

Example 3

The dissolution profile for the exemplary dosage forms is determinedaccording to one or more of the following methods. In some embodiments,U.S.P. method <711> entitled “Dissolution” is followed and any of theconditions below using Apparatus 1, 2, or 3 is followed.

-   -   USP Apparatus Type I dissolution (basket) at 100 rpm in purified        water at 37°;    -   USP Apparatus Type II dissolution (paddles), in 900 ml of HCl        0.1N maintained at a temperature of 37±0.5° C.;    -   USP Apparatus Type II dissolution (paddles), first in 700 ml of        HCl 0.1N maintained at a temperature of 37±0.5° C., during 1        hour, and then in 900 ml phosphate buffer pH 6 with 0.5-1% tween        80 or sodium lauryl sulfate;    -   USP Apparatus Type II dissolution (paddles), in 900 ml of HCl        0.1N at 50 rpm maintained at a temperature of 37±0.5° C.;    -   USP Apparatus Type II dissolution (paddles), in 900 ml of HCl        0.1N with 0.1% tween, maintained at a temperature of 37±0.5° C.;    -   USP Apparatus Type II dissolution (paddles), first in 900 ml of        HCl 0.1N maintained at a temperature of 37±0.5° C., during 1        hour, and then the medium is adjusted to pH 6 with 1% tween;    -   USP Apparatus II dissolution with an ss helix sinker at 50 rpm        in a volume of 900 ml of 0.001 N HCl;    -   USP Apparatus Type III dissolution (reciprocating cylinder), in        distilled water (250 ml, 30 DPM at 37° C.).

Example 4

An osmotic device according to Example 1 or 2 was evaluated to determineits safety, tolerability and pharmacokinetic performance afteradministration of a single dose. The study was an open label, balanced,randomized, two-period, two-sequence, single oral dose, bioavailabilitystudy of Arbaclofen Extended Release Tablets (AERT), 20 mg in normal,healthy, adult human subjects under fasting and fed conditions, with ascreening period of 28 days prior to the dosing in Period-I. In eachstudy period, 18 blood samples (4 mL each), including pre-dose bloodsample were collected from each subject to analyze the pharmacokineticprofile of the ARBAC. For efficacy evaluations, a total of 18 bloodsamples were collected in each period at the time points specified inthe protocol. Standard non-compartmental pharmacokinetic parameters werederived for R-baclofen.

Safety was assessed from the screening period to the end of the study.It was assessed through physical examination, health status evaluation,vital signs assessment, 12-lead Electrocardiogram (ECG), Clinicallaboratory parameters (e.g. biochemistry, hematology, immunology andurine analysis), pregnancy test (for female subjects), subjectivesymptomotology and monitoring of adverse events.

Dosing under fasting condition: After an overnight fast of at least 10hours, a single oral dose of the test product (Arbaclofen ExtendedRelease Tablets, 20 mg) was administered to the subjects with 240 mL ofdrinking water at ambient temperature in sitting posture.

Dosing under fed condition: After an overnight fast of at least 10hours, the subjects were served high fat, high calorie meal, which theywere required to consume within 30 minutes. A single oral dose of thetest product (Arbaclofen Extended Release Tablets, 20 mg) wasadministered to the subjects at 30 minutes after serving the high fatmeal. The IMP was administered in sitting posture with 240 mL ofdrinking water at ambient temperature. The dosing activity was followedby a mouth and hands check to assess the compliance to dosing. The IMPadministration was as per the randomization schedule and under openlabelconditions.

Data from this study demonstrated that the test drugs were welltolerated. There were no deaths or serious AEs during the conduct of thestudy. There were no clinically significant findings in the vital signsassessment, ECG recording or the laboratory tests in any of thesubjects. Pharmacokinetic results are summarized above.

Example 5

An Open Label, Balanced, Randomized, Two-Treatment, Two-Period,Two-Sequence, Cross-Over Bioavailability Study of Arbaclofen ExtendedRelease Tablets, 20 mg (20 mg BID) Compared to the Plasma Profiles andPharmacokinetic Parameters of Baclofen Tablets, USP, 20 mg (20 mg QID)After Multiple Dosing at Steady State in Healthy, Adult, Human SubjectsUnder Fasting Conditions.

The primary objective was to determine the relative bioavailability ofthe Test Product (T) (Arbaclofen Extended Release Tablets, 20 mg (20 mgBID)) compared to the Reference product (R) (Baclofen Tablets, USP, 20mg (20 mg QID)), as measured by plasma profiles and pharmacokineticsparameters, after multiple dosing at steady-state in healthy, adult,human subjects under fasting conditions.

The secondary objective of the study was to evaluate the safety andtolerability at steady state after multiple dose administration ofArbaclofen ER Tablets, 20 mg BID in healthy, adult, human subjects underfasting condition.

The study was an open label, balanced, randomized, two-sequence,two-treatment, two-period, multiple dose, crossover, steady state oralbioavailability study in healthy, adult, human subjects under fastingconditions. In each study period, 24 blood samples (including 3 pre-dosesamples on Day 3, 4 & 5 prior to the morning dose and 21 post-dosesamples on Day 5), were collected from each subject except for thedismissed/discontinued subject and missing samples, to analyze thepharmacokinetic profile of the test as well as the reference drug.

Dosing Regimen for Test Product-T: A single oral dose (20 mg) of TestProduct (T) was administered to the subjects with 240 mL of drinkingwater at ambient temperature in sitting posture. This activity wasfollowed by mouth and hands check to ensure drug ingestion. The IMPadministration was as per the randomization schedule and under openlabel conditions. The dosing was repeated every 12 hours for 5 days. OnDay 5, only the morning dose was administered. Subjects received 9tablets over 5 days (20 mg BID). For all morning doses, subjects fastedfor a minimum of 8 hours pre-dose and 2 hours post-dose. For otherdoses, a minimum of 2 hours pre-dose and 1 hour post-dose fasting wasrequired. Lunch was provided at 4.25 hours post-dose. Dinner and eveningsnack were provided at 8 hours and 13 hours post-dose, respectively. Thedosing was repeated ever 12 hours for 5 days. On Day 5, only the morningdose was administered. Subjects received 9 tablets over 5 days (20 mgBID).

Dosing Regimen for Reference Product-R: A single oral dose (20 mg) ofReference Product (R) was administered to the subjects with 240 mL ofdrinking water at ambient temperature in sitting posture. This activitywas followed by mouth and hands check to ensure drug ingestion. The IMPadministration was as per the randomization schedule and underopen-label conditions. The dosing was repeated every 6 hours for 5 days.On Day 5, only the first two doses were administered. Subjects received18 tablets over 5 days (20 mg QID). For all morning doses, subjectsfasted for a minimum of 4 hours pre-dose and 2 hours post-dose. Forother doses, a minimum of 2 hours pre-dose and 1 hour post-dose fastingwas required. Lunch was provided at 3 hours post-dose. Dinner andevening snack were provided at 8 hours and 13 hours post-dose,respectively. The dosing was repeated every 6 hours for 5 days. On Day5, only the first two doses were administered. Subjects received 18tablets over 5 days (20 mg QID). A washout period of 07 days wasmaintained between the last dose in Period-I and the first dose inPeriod-II.

Data from this study demonstrated that the test and the reference drugswere well tolerated. There were no deaths or serious AEs during theconduct of the study. Pharmacokinetic results are summarized above.

Example 6

A Bioavailability Study of Arbaclofen Extended Release Tablets, 10 mg,15 mg, 20 mg Compared to 20 mg Arbaclofen Solution Administered as aSingle Dose Under Fasting Condition.

The purpose of this study was to determine the relative bioavailabilityof Arbaclofen Extended Release tablets 10 mg, 15 mg, and 20 mg comparedto Arbaclofen Solution 20 mg in healthy, adult, human volunteers of bothgenders after a single dose under fasting conditions and to evaluate thesafety and tolerability after single dose administration of ArbaclofenExtended Release Tablets 10 mg, 15 mg, and 20 mg in healthy humanvolunteers.

The study was an open label, balanced, randomized, four-periodsfour-sequence, single oral dose, crossover, bioavailability in normal,healthy, adult human subjects under fasting conditions, with a screeningperiod of 28 days prior to the first dose administration. In each studyperiod, 18 blood samples (4 mL each), were collected from each subjectexcept for the dismissed subjects and missing sample, to analyze thepharmacokinetic profile of the test as well as the reference product

After an overnight fast of at least 10 hours, the subjects were dosedwith either of the compositions mentioned below. The administration wasas per the randomization schedule and under open-label conditions.

-   -   Test Product (T1): 1 Arbaclofen Extended Release Tablet 10 mg        with 240 mL of ambient temperature water. (Treatment dose=10 mg)    -   Test Product (T2): 1 Arbaclofen Extended Release Tablet 15 mg        with 240 mL of ambient temperature water. (Treatment dose=15 mg)    -   Test Product (T3): 1 Arbaclofen Extended Release Tablet 20 mg        with 240 mL of ambient temperature water. (Treatment dose=20 mg)    -   Reference Product (R): 5 mL of Arbaclofen Solution, 20 mg/5 mL        with 240 mL of ambient temperature water. (Treatment dose=20 mg)

Data from this study demonstrated that the test and the referenceproducts were well tolerated. There were no deaths or serious AEs duringthe conduct of the study. Pharmacokinetic results are summarized above.

Example 7

A Randomized, Double-Blind, Parallel Group Study to Compare the Safetyand Efficacy of Increasing Doses of Arbaclofen Extended Release Tablets(10, 15 or 20 mg BID) to Placebo and Baclofen Tablets, USP (10, 15 and20 mg, QID) for the Treatment of Spasticity in Patients with MultipleSclerosis.

Primary objectives include comparison of the efficacy of arbaclofenextended release tablets (AERT) to placebo on both the CGIC and theTNmAS across a range of doses and of the safety and tolerability of AERTto placebo over 12 weeks of treatment. Secondary objectives includecomparison of AERT to Baclofen Tablets, USP across a range of dosesbased on; 1) efficacy as assessed by the TNmAS, CGIC, and MSSS-88scales, and 2) safety as assessed by the DNRS, ESS, the rate ofspontaneously reported somnolence and premature discontinuations due toAEs. Secondary objectives also include comparison of the efficacy ofAERT 20 mg and 30 mg daily doses to placebo based on the TNmAS and CGICscales. Abbreviations: a) MSSS-88—(88-item Multiple Sclerosis SpasticityScale) assessment is not an evaluation of spasticity, but is intended todetermine the effect spasticity has on the daily life of the subject; b)EDSS—(Expanded Disability Status Scale)—is a method of quantifyingdisability in multiple sclerosis and monitoring changes in the level ofdisability over time; c) LEMMT—(lower extremity manual muscle testingand rating scale)—a procedure for the evaluation of the function andstrength of individual muscles and muscle groups based on effectiveperformance of limb movement in relation to the forces of gravity andmanual resistance; d) CGIC—(Clinical Global Impression ofChange)—developed for use in NIMH-sponsored clinical trials to provide abrief, standalone assessment of the clinician's view of the subject'sglobal functioning prior to and after initiating a study medication, andis used to measure the overall change in the subject's condition sincestarting the study; e) TNmAS—(total numeric-transformed modifiedAshworth scale); f) DNRS (drowsiness numeric rating scale); and g) ESS(Epworth Sleepiness Scale).

This study compares the efficacy and safety of three (3) different AERTdoses (20 mg/day, 30 mg/day and 40 mg/day) with Baclofen Tablets, USP(40 mg/day, 60 mg/day and 80 mg/day) and matching placebo over a 2-weekperiod for each dose (lower, medium and higher), and over a 12-weekmaintenance period that begins at visit 5 and ends at visit 9 for thehigher dose strengths.

Eligible subjects will be enrolled and undergo a two to four (2-4) weekwashout period for withdrawal of all medication used for anti-spasticityand/or muscle relaxation. If the subject is receiving disease-modifyingmedications, these must have been at a stable dose for at least three(3) months prior to screening, and the subject must be willing tomaintain this treatment for the duration of the study. At visit 2, thebaseline clinical evaluation is performed to confirm eligibility forstudy randomization. If subjects meet the randomization criteria, theywill be assigned to one of the three treatment arms (AERT or BaclofenTablets, USP or Placebo). During the first week of drug administration,subjects are up titrated to achieve the first (lower) therapeutic dose.The Dose Response Period begins after visit 3 during which subjects willremain for two (2) weeks at each dose of the two lower doses, having aclinical evaluation at the end of the corresponding phase and then, doseis increased for the following two (2) weeks (V4, V5 and V6) until themaximum dose is achieved. From V3 to V4 subject will stay at the lowertherapeutic dose. From visit 4 to visit 5 subjects are increased to theintermediate therapeutic dose. Finally, from visit 5 to visit 6,subjects will receive the maximum therapeutic dose. After visit 6, themaximum dose is maintained for another ten (10) weeks (the MaintenancePhase) with two (2) visits (V7 and V8) resulting in a total of twelve(12) weeks treatment at the maximum therapeutic fixed dose. Finally,after the last clinical evaluation, visit 9, a two (2) week period fordown titration and withdrawal from study medication is performed,followed by clinical follow-up (visit 10).

AERT (10, 15 or 20 mg) are orally administered Q12h. Reference IRover-encapsulated tablets of rac-BAC (10, 15 or 20 mg) are orallyadministered QID.

Results indicate the dosage forms of the invention are safe, welltolerated and efficacious. There were no deaths or serious AEs duringthe conduct of the study. Of 354 randomized subjects, 59.0% hadrelapsing remitting and 36.7% had secondary progressive MS. The averagebaseline TNmAS score was 7.78. TNmAS and CGIC were statisticallysignificant in favor of AERT group compared with placebo, whiledifferences between AERT and baclofen were not statisticallysignificant. MS Spasticity Scale (MSSS-88) showed a statisticallysignificant improvement in AERT group compared with placebo. EpworthSleepiness Scale (ESS) showed a statistically significant increase insleepiness in the baclofen group, but not in the AERT group compared toplacebo. Drowsiness and dizziness were less frequent in AERT groupcompared with baclofen.

Example 8

A One Year, Open Label, Dose Escalation Study To Evaluate the Long-TermSafety of Arbaclofen Extended Release Tablets (AERT, 10, 15 or 20 mgtablets BID) in Multiple Sclerosis Subjects with Spasticity.

This is a multicenter, open-label, non-randomized dose escalation studyin which the arbaclofen dose for each individual subject will betitrated up to the highest tolerated dose not exceeding 40 mg per day.Once this Maintenance Dose is achieved, each subject will be maintainedon that dose for 1 year. All subjects will begin oral treatment witharbaclofen at 20 mg per day (2×10 mg) for two weeks, then increase to 30mg per day (2×15 mg) for two weeks, and then increase to 40 mg per day(2×20 mg) based on Dose Escalation Criteria. Once the subject reachesthe Maintenance Dose, they will remain on that dose for approximately 1year. The Maintenance Dose is the highest tolerated dose, not to exceed40 mg per day. During the course of the trial, the subject's healthstatus may change so that the clinician and subject may wish to try alower or higher dose of open-label AERT. Changes in the dose of AERT inresponse to changes in a subject's clinical status are permitted andwill be documented in the CRF.

Results indicate the dosage forms of the invention are safe, welltolerated and efficacious. There were no deaths or serious AEs duringthe conduct of the study. The study enrolled 184 subjects, 63% werefemale, mean age was 48 years, average duration of MS diagnosis was 12years, and mean baseline TNmAS score of 6.29. The most common adverseevents (AEs) reported were muscle weakness (13%), somnolence (9.80%),dizziness (8.7%), incontinence (fecal 7.1%, urinary 6.5%), urgency(7.1%), pollakiuria (6.5%), asthenia (6%), and nausea (6%). AEs led tostudy discontinuation in 9.8% of subjects. No effects on laboratoryparameters, vital signs, or ECGs were observed. TNmAS score decreasedduring the up-titration period, and remained consistent during themaintenance period. The improvement in spasticity was greater insubjects receiving 30 & 40 mg/day compared to 20 mg/day.

Example 9

The procedures Examples 1 or 2 are used to prepare a controlled releasedevice containing GABA_(B) receptor agonist as active ingredient in thecore. The osmotic device tablets contain the following ingredients inthe amounts indicated:

Ingredient % wt % wt % wt Core Active  4-12  6-11  7-10 Osmotic Agent30-45 30-40 32-40 Filler 3-7 3.5-6.5 4-5 Binder  5-15  9-13 10-12Swellable Polymer 1 0.1-5   0.5-4   1-3 Swellable Polymer 2 30-45 35-4135-40 Antioxidant 0.01-0.1  0.01-0.1  0.01-0.1  Glidant 0.01-0.5 0.01-0.5  0.01-0.5  Lubricant 0.01-0.5  0.01-0.5  0.01-0.5  Core weightSemipermeable membrane Rate film forming 20-50% 20-40% 25-30% Polymer 1(mg) Rate film forming 80-50% 80-60% 70-60% Polymer 2 (mg) Plasticizer0.1-10%   1-10% 3-9%

Exemplary osmotic devices of the above contain about 5 mg, about 10 mg,about 15 mg or about 20 mg of arbaclofen. The semipermeable membrane mayor may not have a preformed passageway.

Example 10

BID methods of administering doses of GABA_(B) receptor agonist incontrolled/extended release dosage forms, wherein at least one of thedosage forms exhibits a positive food effect, are provided. This methodis suitable for twice or thrice daily oral administration. Either one orboth of the dosage forms may exhibit a positive food effect whenadministered with a high calorie-high fat meal.

Fasting

A subject fasts from food for a period of at least two hours, at leastthree hours or at least four hours and is then orally administered adose of GABA_(B) receptor agonist in a controlled/extended releasedosage form exhibiting a positive food effect. The subject continues tofast for a period of at least one, at least 1.5, at least two or atleast three hours after administration.

Fed

A subject is orally administered a dose of GABA_(B) receptor agonist ina controlled/extended release dosage form exhibiting a positive foodeffect. The dose is administered: a) during a period of no more thanabout 2, no more than about 1.5, no more than about 1, no more thanabout 0.75, no more than about 0.5 or no more than about 0.25 hoursbefore eating; or b) during a period of no more than 2, no more than1.5, no more than 1, no more than 0.75, no more than 0.5 or no more than0.25 hours after having eaten; or c) during the period in which thesubject is eating.

Fed then Fasting

A subject is orally administered a dose according to the above “fed”method. After about 8 to about 16 hours, the subject is orallyadministered a dose according to the above “fasting” method. The subjectmay or may not eat one or more additional meals between the “fed”administration and the “fasting” administration.

Fasting then Fed

A subject is orally administered a dose according to the above “fasting”method. After about 8 to about 16 hours, the subject is orallyadministered a dose according to the above “fed” method. The subject mayor may not eat one or more additional meals between the “fasting”administration and the “fed” administration.

Fed then Fed

A subject is orally administered a dose according to the above “fed”method. After about 8 to about 16 hours, the subject is orallyadministered a dose according to the above “fed” method. The subject mayor may not eat one or more additional meals between the two “fed”administrations.

Fasting then Fasting

A subject is orally administered a dose according to the above “fasting”method. After about 8 to about 16 hours, the subject is orallyadministered a dose according to the above “fasting” method. The subjectmay or may not eat one or more additional meals between the two“fasting” administrations.

Example 11

A wet or dry granulation method is followed to form the compressed core.A coating method is followed to form the membrane surrounding the core.The coated tablets so formed comprise the following ingredients in theamounts indicated:

Ingredient % wt % wt % wt % wt % wt % wt Core ARBAC  4-12  4-12  4-12 4-12  2-15  5-11 NaCl or mannitol 30-45 25-45 25-45 30-40 10-40 30-40MCC  5-10  5-10  5-15  1-10  1-20  1-10 Povidone or 10-20 10-20  5-2510-20 10-20  5-15 copovidone Swellable HPMC 0.5-5   0.5-5   0.1-7.5 1-51-5 2-7 Swellable PEO 25-50 25-50 25-50 25-40 25-35 30-45 Optional0.01-0.5  0.01-0.5  0.01-0.5  0.01-0.5  0.01-0.5  0.01-0.5  AntioxidantOptional Glidant 0.01-0.5  0.01-0.5  0.01-0.5  0.01-0.5  0.01-0.5 0.01-0.5  Optional Lubricant 0.01-0.5  0.01-0.5  0.01-0.5  0.01-0.5 0.01-0.5  0.01-0.5  Semipermeable membrane Rate film forming ≦20 ≦1060-40 20-40 25-35 Polymer 1 Rate film forming ≧80 ≧90 40-60 60-80 60-70Polymer 2 Plasticizer 0.1-10  0.1-10  0.1-10  0.1-10  0.1-10 

All different combinations of the core formulations and membraneformulations above can be used. Exemplary osmotic devices of the abovecontain about 5 mg, about 10 mg, about 15 mg or about 20 mg ofarbaclofen. The semipermeable membrane may or may not have a preformedpassageway.

All values disclosed herein may have standard technical measure error(standard deviation) of ±10%. The term “about” is intended to mean±10%,±5%, ±2.5% or ±1% relative to a specified value, i.e. “about” 20% means20±2%, 20±1%, 20±0.5% or 20±0.25%.

It should be noted that, unless otherwise specified, values hereinconcerning pharmacokinetic or dissolution parameters are typicallyrepresentative of the mean or median values obtained from evaluation ofat least 4, at least 8 or at least 12 of the same dosage forms.

The above is a detailed description of particular embodiments of theinvention. It will be appreciated that, although specific embodiments ofthe invention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims. All of the embodiments disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure.

1) A controlled release oral dosage form comprising: a) a corecomprising at least one GABA_(B) receptor agonist and at least oneexcipient; and b) a semipermeable membrane surrounding the core andcomprising at least one preformed passageway. 2) The dosage form ofclaim 1, wherein: a) the core comprises at least one GABA_(B) receptoragonist and at least two water-swellable excipients; and b) thesemipermeable membrane surrounding the core comprises at least twofilm-forming cellulose esters and at least one preformed passageway. 3)The dosage form of claim 1, wherein: a) the core comprises at least oneGABA_(B) receptor agonist, at least two water-swellable excipients, andat least one osmotic salt; and b) the semipermeable membrane surroundingthe core comprises at least two film-forming cellulose esters and atleast one preformed passageway. 4) The dosage form of claim 1, wherein:a) the core comprises at least one GABA_(B) receptor agonist, at leasttwo water-swellable excipients, at least one osmotic salt, and at leastone binder, and b) the semipermeable membrane surrounding the corecomprises at least two film-forming cellulose esters and at least onepreformed passageway. 5) The dosage form of claim 4, wherein the atleast two water-swellable excipients comprise a combination of acellulose derivative and polyalkylene oxide. 6) The dosage form of claim2, wherein the at least two water-swellable excipients comprise a majorportion of a first type and a minor portion of a second type of polymer.7) The dosage form of claim 2, wherein the at least two film-formingcellulose esters are present as: a) a combination of at least twodifferent grades of the same type of cellulose ester polymer; or b) acombination of two different types of cellulose ester polymer. 8) Thedosage form of claim 1, wherein the dosage form exhibits a sigmoidal invitro release profile as follows under conditions defined in USP <711>using a Type II apparatus with 0.1 N HCl stirred at 50 rpm andmaintained at a temperature of 37±0.5° C., wherein about 60 to about100% wt of the drug is released over a period of about 6 to about 16hours. 9) The dosage form of claim 8, wherein about 40 to about 80% wtof the drug is released after six hours, about 55 to about 100% of thedrug is released after 8 hours, and no less than 70% of the drug isreleased after 12 hours, or wherein about 45 to about 85% wt of the drugis released after six hours, about 65 to about 100% of the drug isreleased after 8 hours, and no less than 75% of the drug is releasedafter 12 hours. 10) The dosage form of claim 1, wherein the dosage formexhibits a sigmoidal in vitro release profile as follows underconditions defined in USP <711> using a Type II apparatus with 0.1 N HClstirred at 50 rpm and maintained at a temperature of 37±0.5° C.Dissolution (% wt) Time (hr) Maximum Minimum 0 0 0 2 20 5 4 50 20 6 8040 8 100 55 12
 70.

11) The dosage form of claim 1, wherein the at least one GABA_(B)receptor agonist is (R)-baclofen (ARBAC) and is not racemic baclofen.12) The dosage form of claim 1, wherein the membrane ruptures from 0.1to 1.5 hours after exposure of the device to an environment of use. 13)The dosage form of claim 12, wherein the rupture occurs adjacent anedge, seam or shoulder of the core. 14) The dosage form of claim 1,wherein the core: a) further comprises at least one binder; b) furthercomprises at least one filler; c) further comprises at least oneantioxidant; d) further comprises at least one glidant; e) furthercomprises at least one lubricant; f) comprises about 5 to about 25 mg ofGABA_(B) receptor agonist; g) has a formulation as described herein; h)is a unitary core; h) comprises a mixture of ingredients; i) is acompressed composition; and/or j) excludes a composition or coat orlayer between the core and the semipermeable membrane. 15) The dosageform of claim 1, wherein the dosage form provides a controlled releaseof GABA_(B) receptor agonist for a period of at least 8 and up to about24 hours. 16) The dosage form of claim 1, wherein the dosage formexhibits a positive food effect in terms of bioavailability, Tmax, Cmax,AUC_(0-t) and/or AUC_(0-inf) when comparing oral administration of thedosage form in the fed and fasting states. 17) The dosage form of claim1, wherein a batch of the dosage forms exhibit a standard deviation inthe range of ±0.05% to ±10% in the release profile of active agent fromthe core on a point-to-point or overall basis. 18) The dosage form ofclaim 11, wherein, following oral administration to a subject in needthereof, the subject exhibits less adverse events associated with ARBACthan if the subject is orally administered an equivalent daily dose ofarbaclofen, present as part of racemic baclofen, in a rapid release orimmediate release dosage form. 19) The dosage form of claim 11, whereinthe dosage form provides a reduced Cmax and/or AUC as compared to oraladministration of a reference immediate release dosage form comprisingthe same dose of ARBAC. 20) The dosage form of claim 11, whereinfollowing oral administration the extended release dosage form providesa Cmax and AUC for ARBAC that is lower than that provided by animmediate release dosage form comprising rac-BAC but the same molaramount of (R)-BAC and still provides substantially the same or animproved clinical benefit over the immediate release dosage form. 21)The dosage form of claim 1, wherein following oral administration thedosage form provides a plasma profile as depicted in FIG.
 2. 22) Thedosage form of claim 1, wherein the dosage form provides a dissolutionprofile as depicted in FIG. 1 inclusive of the area defined by minimumand maximum profiles. 23) The dosage form of claim 1, wherein the dosageform has a cross-sectional structure substantially as depicted in FIGS.3, 4A and 4B. 24) The dosage form of claim 1, wherein oraladministration of said controlled release dosage form, in the fed state,comprising a 20 mg dose of GABA_(B) receptor agonist provides apharmacokinetic profiled defined as follows Mean values Tmax (hr) about4-6 Cmax (ng/ml) about 110-190 AUC (ng · h/ml) about 1400-1900.

25) The dosage form of claim 1, wherein oral administration of saidcontrolled release dosage form in the fasting state comprising a 20 mgdose of GABA_(B) receptor agonist provides a pharmacokinetic profileddefined as follows Mean values Tmax (hr) about 3.5-5.5 Cmax (ng/ml)about 80-150 AUC (ng · h/ml) about 550-1080.

26) The dosage form of claim 1, wherein oral administration of saidcontrolled release dosage form in the fed state comprising a 20 mg doseof GABA_(B) receptor agonist provides a steady state pharmacokineticprofiled defined as follows Mean values Tmax_(ss) (hr) 4-6 Cmax_(ss)(ng/ml) about 120-220 Cmin_(ss) (ng/ml) about 10-100 AUC_(ss) (ng ·h/ml) about 1000-1700.

27) The dosage form of claim 1, wherein oral administration of saidcontrolled release dosage form in the fasting state comprising a 20 mgdose of GABA_(B) receptor agonist provides a steady statepharmacokinetic profiled defined as follows Mean values Tmax_(ss) (hr)3.5-5.5 Cmax_(ss) (ng/ml) about 80-150 Cmin_(ss) (ng/ml) about 5-80AUC_(ss) (ng · h/ml) about 600-1150.

28) The dosage form of claim 1, wherein oral administration of saidcontrolled release dosage form in the fasting state comprising thespecified dose of GABA_(B) receptor agonist provides a pharmacokineticprofiled defined as follows Parameter 10 mg dose 15 mg dose 20 mg doseTmax (hr) (median about 5 about 4.5 About 5 or mean) Cmax (ng/ml) about77 about 100 About 142 AUC_(0-inf) (ng · h/ml) About 575 About 700 About1090.

29) The dosage form of claim 1, wherein following oral administrationthe dosage form provides a majority of drug release in the upper portionof the GI tract. 30) The dosage form of claim 11, wherein following oraladministration the dosage form provides reduced adverse events ascompared to oral administration of a rapid release or immediate releasedosage form containing an equimolar amount of arbaclofen which may bepresent as racemic baclofen.